Evidence Report/Technology Assessment 

Number 164 

Utility of Monitoring Mycophenolic Acid in Solid Organ 

Transplant Patients 

Prepared for: 

Agency for Healthcare Research and Quality 

U.S. Department of Health and Human Services 

540 Gaither Road 

Rockville, MD 20850 

www.ahrq.gov 

Contract No. 290-02-0020 

Task Order Leader: 

Parminder Raina, Ph.D. 

Director, McMaster University Evidence-based Practice Center 

Co-Principal Investigators: 

Mark Oremus, Ph.D. 

Johannes Zeidler, Ph.D., D.A.B.C.C. 

Authors: 

Mark Oremus, Ph.D. 

Johannes Zeidler, Ph.D., D.A.B.C.C. 

Mary H.H. Ensom, Pharm.D., F.A.S.H.P., F.C.C.P., F.C.S.H.P. 

Mina Matsuda-Abedini, M.D.C.M., F.R.C.P.C. 

Cynthia Balion, Ph.D., F.C.A.C.B. 

Lynda Booker, B.A.

Carolyn Archer, M.Sc. 

Parminder Raina, Ph.D. 

AHRQ Publication No. 08-E006 

February 2008 
This report is based on research conducted by the McMaster University Evidence-based Practice 

Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), 

Rockville, MD (Contract No. 290-02-0020). The findings and conclusions in this document are 

those of the author(s), who are responsible for its content, and do not necessarily represent the 

views of AHRQ. No statement in this report should be construed as an official position of AHRQ 

or of the U.S. Department of Health and Human Services. 

The information in this report is intended to help clinicians, employers, policymakers, and others 

make informed decisions about the provision of health care services. This report is intended as a 

reference and not as a substitute for clinical judgment. 

This report may be used, in whole or in part, as the basis for the development of clinical practice 

guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage 

policies. AHRQ or U.S. Department of Health and Human Services endorsement of such 

derivative products may not be stated or implied. 
ii

This document is in the public domain and may used and reprinted without permission except 

those copyrighted materials noted for which further reproduction is prohibited without the 

specific permission of copyright holders. 

Suggested Citation: 

Oremus M, Zeidler J, Ensom MHH, Matsuda-Abedini M, Balion C, Booker L, Archer C, Raina 

P. Utility of Monitoring Mycophenolic Acid in Solid Organ Transplant Patients. Evidence 

Report/Technology Assessment No. 164. (Prepared by the McMaster University Evidence-based 

Practice Center, under Contract No. 290-02-0020.) AHRQ Publication No.08-E006. Rockville, 

MD: Agency for Healthcare Research and Quality. February 2008. 

 

Financial Disclosure Statement: 

Dr. Matsuda-Abedini is the principal investigator for a research project with operational costs 

funded by Novartis. No other authors of this report have any financial or business interest in 

this field. 
iii

Preface 

 The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based 

Practice Centers (EPCs), sponsors the development of evidence reports and technology 

assessments to assist public- and private-sector organizations in their efforts to improve the 

quality of health care in the United States. The reports and assessments provide organizations 

with comprehensive, science-based information on common, costly medical conditions and new 

health care technologies. The EPCs systematically review the relevant scientific literature on 

topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to 

developing their reports and assessments. 

 To bring the broadest range of experts into the development of evidence reports and health 

technology assessments, AHRQ encourages the EPCs to form partnerships and enter into 

collaborations with other medical and research organizations. The EPCs work with these partner 

organizations to ensure that the evidence reports and technology assessments they produce will 

become building blocks for health care quality improvement projects throughout the Nation. The 

reports undergo peer review prior to their release. 

 AHRQ expects that the EPC evidence reports and technology assessments will inform 

individual health plans, providers, and purchasers as well as the health care system as a whole by 

providing important information to help improve health care quality. 

 We welcome comments on this evidence report. They may be sent by mail to the Task Order 

Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, 

Rockville, MD 20850, or by e-mail to epc@ahrq.gov. 

Carolyn M. Clancy, M.D. Jean Slutsky, P.A., M.S.P.H. 

Director Director, Center for Outcomes and Evidence 

Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality 

Beth A. Collins Sharp, PhD., R.N. Ernestine Murray, B.S.N., R.N., M.A.S. 

Director, EPC Program Task Order Officer, EPC Program 

Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality 
iv

Acknowledgments

We thank the representatives of our partner organization, the American Association for Clinical 

Chemistry, Dr. Susan Maynard and Dr. Robert Christenson. We are grateful to members of the 

technical expert panel who were instrumental in developing the questions and defining the scope 

of this review: Dr. Klemens Budde, Dr. Guido Filler, Dr. Atholl Johnston, Dr. Les Shaw, and Dr. 

Maria Shipkova. 

Our thanks go to librarian Maureen Rice for her thorough management of the search terms and 

methodology. We would like to thank the following people who helped with the data abstraction 

for this review: Connie Freeborn, Rob Stevens, Carolina Ruiz Culebro, Alok Gupta, and Paula 

Robinson.

Our editorial staff, Cecile Royer, Roxanne Cheeseman, and Sarah Smith, have provided 

invaluable input into this document. 
v

Structured Abstract 

Objectives: To investigate whether monitoring concentrations of mycophenolic acid (MPA) in 

the serum or plasma of persons who receive a solid organ transplant will result in a lower 

incidence of transplant rejections and adverse events versus no monitoring of MPA. To 

investigate whether the incidence of rejection or adverse events differs according to MPA dose 

or frequency, type of MPA, the form of MPA monitored, the method of MPA monitoring, or 

sample characteristics. To assess whether monitoring is cost-effective versus no monitoring. 

Data Sources: The following databases were searched from their dates of inception (in brackets) 

until October 2007: MEDLINE® (1966); BIOSIS® Previews (1976); EMBASE® (1980); 

Cochrane Database of Systematic Reviews® (1995); and Cochrane Central Register of 

Controlled Trials® (1995). 

Review Methods: Studies identified from the data sources went through two levels of screening 

(i.e., title and abstract, full text) and the ones that passed were abstracted. Criteria for abstraction 

included publication in the English language, study design (i.e., randomized controlled trial 

[RCT], observational study with comparison group, case series), and patient receipt of allograft 

solid organ transplant. Additionally, any form of MPA had to be measured at least once in the 

plasma or serum using any method of measurement (e.g., AUC0-12, C0). Furthermore, these 

measures had to be linked to a health outcome (e.g., transplant rejection). Certain biomarkers 

(e.g., serum creatinine, glomular filtration rate) and all adverse events were also considered 

health outcomes. 

Results: The published evidence on MPA monitoring is inconclusive. Direct, head-to-head 

comparison of monitoring versus no monitoring is limited to one RCT in adult, kidney transplant 

patients. Inferences about monitoring can be made from some observational studies, although 

the evidence is equivocal for MPA dose and dose frequency, nonexistent for type of MPA, 

inconclusive for form of MPA monitored or method of monitoring, and nonexistent for costeffectiveness. Some studies suggest gender and concomitant use of calcineurin inhibitors will 

affect pharmacokinetic parameters, but the impact of these findings has not been assessed in 

relation to monitoring versus no monitoring. 

Conclusion: The state of knowledge about therapeutic drug monitoring of MPA in solid organ 

transplants is still in its infancy. Until there is more evidence on the utility of routine MPA 

monitoring in solid organ transplant recipients, patients, clinicians, and other stakeholders (e.g., 

public and private insurers) will have to decide on a case by case basis whether the possible but 

uncertain benefits are worth the extra time and expense of monitoring. 

vii

Contents 

Executive Summary........................................................................................................................... 1 

Evidence Report............................................................................................................................... 9

Chapter 1. Introduction .................................................................................................................... 11 

Mycophenolic Acid ...................................................................................................................... 11 

Solid Organ Transplant................................................................................................................. 12 

Mycophenolic Acid: Use in Solid Organ Transplants.................................................................. 12 

Therapeutic Drug Monitoring of Mycophenolic Acid ................................................................. 14 

Scope and Purpose of the Evidence Report.................................................................................. 15 

Chapter 2. Methods.......................................................................................................................... 17 

Analytic Framework..................................................................................................................... 17 

Topic Assessment and Refinement .............................................................................................. 17

Research Team.......................................................................................................................... 17 

Technical Expert Panel Teleconference Calls .......................................................................... 18 

General Methods .......................................................................................................................... 20 

Key Questions ........................................................................................................................... 20 

Literature Search Strategy......................................................................................................... 20 

Data Collection and Reliability of Study Selection .................................................................. 21 

Quality Assessment of Included Studies................................................................................... 22 

Summary of Findings: Descriptive and Analytic Approaches.................................................. 22 

Peer Review Process..................................................................................................................... 22 

Chapter 3. Results ............................................................................................................................ 23 

Literature Review and Screening ................................................................................................. 23 

Key Questions .............................................................................................................................. 23 

Question 1. What is the Evidence That Monitoring Mycophenolic Acid in Patients who 

 Receive a Solid Organ Transplant Results in a Lower Incidence of Transplant 

 Rejections and Adverse Events Compared to Patients who are not Monitored?................. 23 

Question 2. Does the Incidence Differ by any of the Following?............................................. 26 

2a: MPA Dose and Dose Frequency.................................................................................... 26 

2b: Type of MPA (mycophenolate mofetil [CellCept®], enteric-coated mycophenolate 

sodium [Myfortic®]) ........................................................................................................... 27 

Question 3a: Does the Incidence Differ by any of the Following?........................................... 27 

Does the Incidence Differ by Albumin versus MPA? ......................................................... 27 

Does the Incidence Differ by Genetic Differences or Metabolite Concentrations? ............ 29 

Does the Incidence Differ by Assay Method? ..................................................................... 31 

Question 3b: Does the Incidence Differ by Method of MPA Monitoring (Full AUC or 

 Limited Sampling Strategies [i.e., Predose Concentrations, 2 hour Post Dose 

 Concentrations, Other])?...................................................................................................... 32 
viii

Question 4. Does the Evidence for Monitoring MPA Differ by any of the Following?........... 37 

4a: Age................................................................................................................................. 37 

4b: Gender............................................................................................................................ 38 

4c: Ethnicity......................................................................................................................... 38 

4d: Concomitant use of Calcineurin Inhibitors (e.g., Tacrolimus, Cyclosporine)............... 39 

4e: Concomitant use of Other Medications ......................................................................... 40 

4f: Comorbidity.................................................................................................................... 40 

Question 4. Summary................................................................................................................ 42 

Question 5. What is the Short- and Long-Term Cost-Effectiveness of Avoiding Acute 

 Rejection due to MPA Monitoring?..................................................................................... 42 

Quality Assessment of Abstracted Studies................................................................................... 42 

Chapter 4. Discussion .................................................................................................................... 113 

Discussion of the Evidence for the Key Questions.................................................................... 113 

Question 1. What is the Evidence That Monitoring Mycophenolic Acid in Patients who 

 Receive a Solid Organ Transplant Results in a Lower Incidence of Transplant 

 Rejections and Adverse Events Compared to Patients who are not Monitored?............... 113 

Question 2. Does the Incidence Differ by any of the Following?........................................... 114 

2a: MPA Dose and Dose Frequency? ................................................................................ 114 

2b: Type of MPA (mycophenolate mofetil [CellCept®], enteric-coated mycophenolate 

sodium [Myfortic®])?........................................................................................................ 114

Question 3a: Does the Incidence Differ by Total Versus Free MPA, Albumin, Metabolites, 

 Genetic Differences or by Analytical Method of MPA Monitoring?................................ 115 

Does the Incidence Differ by Genetic Differences or Metabolite Concentrations? .......... 115 

Does the Incidence Differ by Assay Method? ................................................................... 116 

Question 3b: Does the Incidence Differ by Method of MPA Monitoring (Full AUC or 

 Limited Sampling Strategies [i.e., Predose Concentrations, 2 hour Post Dose 

 Concentrations, Other])?.................................................................................................... 117 

Question 4. Does the Evidence for Monitoring MPA Differ by any of the Following–Age, 

 Gender, Ethnicity, Concomitant use of Calcineurin Inhibitors, Concomitant use of 

 Other Medications, Comorbidity? ..................................................................................... 118 

Question 5. What is the Short- and Long-Term Cost-Effectiveness of Avoiding Acute 

 Rejection due to MPA Monitoring?................................................................................... 119 

Limitations of This Evidence Report ......................................................................................... 119

Conclusions ................................................................................................................................ 120 

References...................................................................................................................................... 123 

List of Acronyms/Abbreviations.................................................................................................... 131 

Figures 

Figure 1. Structural Formula for Mycophenolate Acid ................................................................... 11 

Figure 2. Analytical Framework...................................................................................................... 17 

Figure 3. Flow diagram showing the number of citations processed at each level of the 

 screening process. ............................................................................................................ 25 
ix

Tables 

Table 1. Studies showing that rejection is related to MMF dosage ............................................... 44 

Table 2. Studies showing that rejection is not related to MMF dosage......................................... 45 

Table 3. Studies showing that adverse events are related to MMF dosage ................................... 47 

Table 4. Studies showing that adverse events are not related to MMF dosage ............................. 50 

Table 5. Association of MPA monitoring with free vs total MPA and albumin ........................... 53 

Table 6. Association of MPA outcomes with metabolites or genes .............................................. 54 

Table 7. Studies showing some relationship between rejection and method of MPA monitoring 56 

Table 8. Studies showing some relationship between rejection and method of MPA monitoring. 

Limited sampling strategies – Predose (C0, Cmin, or C12) ............................................ 59 

Table 9. Studies showing some relationship between rejection and method of MPA monitoring. 

Limited sampling strategies - 2h Post (C2)...................................................................... 63 

Table 10. Studies showing some relationship between rejection and method of MPA. Limited 

sampling strategies - Other .............................................................................................. 64 

Table 11. Studies showing no relationship between rejection and method of MPA monitoring .... 67 

Table 12. Studies showing no relationship between rejection and method of MPA monitoring. 

Limited sampling strategies – Predose (C0, Cmin, or C12) ............................................ 68 

Table 13. Studies showing no relationship between rejection and method of MPA monitoring. 

Limited sampling strategies - 2h post (C2)...................................................................... 75 

Table 14: Studies showing no relationship between rejection and method of MPA monitoring. 

Limited sampling strategies - Other................................................................................. 76 

Table 15. Studies showing some relationship between graft function or other efficacy parameter 

and method of MPA monitoring...................................................................................... 78 

Table 16. Studies showing no relationship between graft function or other efficacy parameter and 

method of MPA monitoring............................................................................................. 79 

Table 17. Studies showing some relationship between adverse events and method of MPA 

monitoring........................................................................................................................ 80 

Table 18. Studies showing some relationship between adverse events and method of MPA 

monitoring. Limited sampling strategies – Predose (C0, Cmin, or C12) ....................... 81 

Table 19. Studies showing some relationship between adverse events and method of MPA 

monitoring. Limited sampling strategies - 2h Post (C2).................................................. 82 

Table 20. Studies showing some relationship between adverse events and method of MPA 

monitoring. Limited sampling strategies - Other............................................................. 83 

Table 21. Studies showing no relationship between adverse events and method of MPA 

monitoring........................................................................................................................ 84 

Table 22. Studies showing no relationship between adverse events and method of MPA 

monitoring. Limited sampling strategies – Predose (C0, Cmin, or C12) ....................... 87 

Table 23. Studies showing no relationship between adverse events and method of MPA 

monitoring. Limited sampling strategies – 2h Post (C2) ................................................. 93 

Table 24. Studies showing no relationship between adverse events and method of MPA 

monitoring. Limited sampling strategies - Other............................................................. 94 

Table 25. Influence of age on the utility of monitoring mycophenolic acid in patients who 

 receive a solid organ transplant........................................................................................ 99 

Table 26. Influence of gender on the utility of monitoring mycophenolic acid in patients who 

receive a solid organ transplant...................................................................................... 101 
x

Table 27. Influence of ethnicity on the utility of monitoring mycophenolic acid in patients who 

receive a solid organ transplant...................................................................................... 102 

Table 28. Influence of the concomitant use of calcineurin inhibitors on the utility of monitoring 

mycophenolic acid in patients who receive a solid organ transplant............................. 103 

Table 29. Influence of the concomitant use of other medications on the utility of monitoring 

mycophenolic acid in patients who receive a solid organ transplant............................. 110 

Table 30. Influence of comorbidity on the utility of monitoring mycophenolic acid in patients 

who receive a solid organ transplant.............................................................................. 112 

Appendixes 

Appendix A: Exact Search Strings 

Appendix B: Forms/Guides 

Appendix C: Evidence Tables 

Appendix D: List of Excluded Studies 

Appendix E: Technical Expert Panel/ Peer Reviewers 

Appendixes and Evidence Tables for this report are provided electronically at 

http://www.ahrq.gov/clinic/tp/mpaorgtp.htm.
11
1

Executive Summary 

Introduction 

Mycophenolic acid (MPA) is an immunosuppressant drug used to prevent rejection of solid 

organ transplants. The drug is marketed as the ester prodrug mycophenolate mofetil 

(MMF)(CellCept®) for kidney, liver, and heart transplants or enteric-coated mycophenolate 

sodium (Myfortic®) (ECMPS) for kidney transplants.1

Therapeutic drug monitoring of MPA has the objective of improving control over acute 

rejection. It is based on observed associations between pharmacokinetic (PK) parameters such as 

total MPA area under the concentration-time curve (AUC0 – 12) and acute rejection in adult and 

pediatric patients.2,3

This evidence report was commissioned to address the following key questions: 

1. What is the evidence that monitoring mycophenolic acid in patients who receive a solid organ 

transplant results in a lower incidence of transplant rejections and adverse events compared to 

patients who are not monitored? 

2. Does the incidence differ by any of the following? 

a) MPA dose and dose frequency;

b) Type of MPA (mycophenolate mofetil [CellCept®], enteric-coated mycophenolate sodium 

[Myfortic®]).

3. a) Does the incidence differ by any of the following? 

ia) Total versus free MPA 

ib) Albumin versus MPA 

iia) MPAG, AcMPAG versus MPA 

iib) Genetic basis of differences in MPA pharmacokinetic parameters 

iii) Assay method (HPLC, EMIT, HPLC-MS, other) 

 b) Does the incidence differ by analytical method of MPA monitoring?

i. Full AUC 

ii. Limited sampling strategies 

a. Predose concentrations 

b. 2h post dose concentrations 

c. Other 

 
2

4. Does the evidence for monitoring MPA differ by any of the following?

a) Age 

b) Gender 

c) Ethnicity 

d) Concomitant use of calcineurin inhibitors (e.g., tacrolimus, cyclosporine) 

e) Concomitant use of other medications 

f) Comorbidity 

5. What is the short- and long-term cost-effectiveness of avoiding acute rejection due to MPA 

monitoring? 

Methods

The following electronic databases were searched up until October 22, 2007: 

1. MEDLINE® (1966-); 

2. BIOSIS® Previews (1976-); 

3. EMBASE® (1980-); 

4. Cochrane Database of Systematic Reviews® (1995-); 

5. Cochrane Central Register of Controlled Trials® (1995-). 

We examined the reference lists of several recently published review articles3-6 and consulted 

with the technical expert panel to identify additional published studies. 

Inclusion/exclusion criteria. We included randomized controlled trials, observational 

studies with comparison groups, or case series, published in the English language. We included 

studies of pediatric and adult patients who received allograft solid organ transplants, provided 

that any form of MPA was measured in serum or plasma, using any method of measurement 

(e.g., AUC). 

Data Collection and Reliability of Study Selection. A team of trained raters applied the 

inclusion and exclusion criteria to the citations identified in the literature search. Each citation 

was screened by two independent raters and had to pass two levels of screening (title and 

abstract, full text) prior to data abstraction. 

Quality Assessment of Included Studies. The methodological quality of included studies 

was assessed independently by two raters using ‘core’ criteria enumerated in the draft Evidencebased Practice Centre Methods Manual (under preparation by the AHRQ). 

Results

The literature search yielded 11,642 citations, from which 495 (4 percent) proceeded to full 

text screening. Of these 495 citations, 89 (18 percent) were included in the report and abstracted. 
3

What is the Evidence That Monitoring Mycophenolic Acid in Patients 

who Receive a Solid Organ Transplant Results in a Lower Incidence 

of Transplant Rejections and Adverse Events Compared to Patients 

who are not Monitored? 

Only three studies addressed this question (four reports).7-10 Patients in the concentrationcontrolled group had fewer rejections than patients in the fixed-dose group in two studies (no pvalue reported in one study; p=0.01 in the other study). In the third study, there were more 

rejections in the concentration-controlled group (p>0.05). 

Does the Incidence Differ by MPA Dose and Dose Frequency? 

Only one study compared rejection outcomes for subjects with planned dose adjustments 

based on different target MPA plasma concentrations.11,12 In this RCT of kidney transplant 

recipients, the incidence of biopsy-proven acute rejection was inversely associated with 

increasing pre-defined MPA AUC concentration-control levels (p=0.043). 

Does the Incidence Differ by Type of MPA (Mycophenolate Mofetil, 

Enteric-coated Mycophenolate Sodium)?

There was no evidence in the included studies to answer this question. 

Does the Incidence Differ by Total versus free MPA, Albumin, Genetic 

Differences, Metabolites? 

Free versus total MPA. The incidence of rejection or adverse events was found to differ 

significantly between free and total MPA in only one13 of nine studies13-21 that examined both 

forms of MPA. 

Albumin. Studies generally found that impaired kidney function and hypoalbuminemia were 

associated with increased concentrations or AUCs of free MPA, but not total MPA. 

Pharmacogenetic. Seven days after transplantation, renal allograft recipients (n=9) without 

the C-24T Single Nucleotide Polymorphisms (SNP) of the multidrug resistance-associated 

protein 2 (MRP2), but with mild liver dysfunction, had lower MPA exposure compared to MRP2 

C-24T non-carriers (n=45) without liver dysfunction. MPA pharmacokinetic (PK) parameters 

were found to vary with the time of the day (daytime AUC > nighttime AUC). No direct 

associations between genotype, MPA PK parameters, and outcomes were found. 

Metabolites. Two15,16 of seven studies15,16,20,22-25 found associations between MPA 

metabolite concentrations and adverse events. Higher median acyl glucuronide metabolite of 

mycophenolic acid (AcMPAG) (p=0.03), mycophenolic acid glucuronide (MPAG) C0

concentrations (p=0.02), and AcMPAG/MPA ratios (p=0.004), but not higher MPA C0

concentrations (p>0.05) were found in patients at times when they experienced anemia versus 

times when with no anemia.15 The authors also found lower median MPAG C0 concentrations at 

times of a leucopenia episode versus times of no episode (p=0.04). In the second study16, a 

correlation was found between the amount of fecal fat loss and MPAG concentrations (r=0.9955, 
4

p<0.001), as well as AcMPAG concentrations (r=0.90, p=0.015) in five renal allograft recipients 

with persistent afebrile diarrhea. 

Does the Incidence Differ by Assay Method?

Only two case series26,27 involved direct comparisons of different assay methods (enzymemultiplied immunoassay technique (EMIT) versus high-performance liquid chromatography 

(HPLC)). Both reports included children with transplanted kidneys from the same research 

project. EMIT and HPLC were equally able to discriminate between patients with acute 

rejections during the first 70 days post-transplant. Decision concentrations, below which the risk 

of acute rejection is increased, were higher with EMIT than with HPLC. None of the PK 

parameters, regardless of assay method, were associated with the incidence of adverse events. 

Does the Incidence Differ by Analytical Method of MPA Monitoring?

Ten studies (11 reports)11,12,17,26-33 showed AUC0-12 to be related to rejection, while 4 studies 

34-37 showed no relation. There were 17 positive studies (18 reports)7,8,12,26,27,30,33,38-48 linking 

(predose, C0, Cmin, or C12) concentration to rejection and 25 negative 

studies.11,15,17,19,24,25,28,36,37,42,45,49-62 Only one study 57found C2 to be a significant predictor of 

rejection while one other study 54 did not. Eleven studies 10,17,19,26,43,49,54,57,59,63,64 found other 

limited sampling strategies (i.e., involving C0, C20min, C30min, C40min, C1, C75min, C2, C3, C4, C6, 

AUC0-9) be related to rejection whereas 9 studies 11,13,17,26,36,51,52,54,65 found no relationship. 

Four studies31,33,36,46 showed that AUC0-12 is associated with adverse effects, while 11 studies (12 

reports)11,12,17,26,29,32,35-37,52,66,67 showed no association. There were 18 studies14,16,33,36,39-

41,45,48,56,61,68-74 demonstrating associations between predose concentration (predose, C0, Cmin, or 

C12) and adverse effects, and 24 studies (25 

reports)11,12,14,15,17,18,20,22,25,26,36,37,42,47,49,52,54,57,62,64,66,67,72,75,76 demonstrating no associations. No 

studies found C2 to be a significant predictor of adverse effects and two54,57 found no association. 

Five studies33,59,65-67 found other limited sampling strategies (C0, C30min, C40min, C1, C3, C6) to be 

associated with adverse effects while 17 studies10,11,13,17,20,21,26,36,49,52,54,57,64,66,75-77 showed the 

opposite. 

Does the Evidence for Monitoring MPA Differ by Age, Gender, 

Ethnicity, Concomitant use of Calcineurin Inhibitors or Other 

Medications, or Comorbidity? 

Some of the six factors of this question appear to influence MPA PK parameters. None of the 

included studies investigated whether PK parameter concentrations, stratified by each factor, 

were associated with outcomes such as rejection or adverse events. Regarding age, the evidence 

was equivocal. In pediatric populations, younger children were found to require a higher MMF 

dose to achieve a specified MPA concentration. When given the same dose of MMF, the MPA 

AUC has been reported to be lower in the elderly compared to younger adults. Regarding gender, 

the evidence appears to indicate that PK parameters are higher for females versus males. Race 

and ethnicity do not appear to influence MPA PK parameters. Calcineurin inhibitors and 

sirolimus are co-administered frequently with MMF and the bulk of the evidence found that 

exposure to MPA is higher in patients receiving tacrolimus or sirolimus compared to 
5

cyclosporine, with lower doses of MMF required in combination with tacrolimus to achieve 

adequate MPA exposure. MPA PK parameters were generally higher in persons with renal 

insufficiency, although one study20 found lowered MPA AUC in the early post-transplant period. 

What is the Short and Long-Term Cost-Effectiveness of Avoiding 

Acute Rejection due to MPA Monitoring? 

None of the abstracted studies contained any data on the cost-effectiveness of MPA 

monitoring. 

Quality Assessment of Abstracted Studies 

Twelve of the 89 abstracted studies were RCTs10-12,25,28,29,34,50,51,65,68,78 and the remainder 

were observational studies (primarily case series). The quality of the RCTs was fair to good, 

although reporting of some essential features of trial design was lacking (e.g., method of 

randomization, blinding). 

Compared to the RCTs, the 77 observational studies suffered from numerous reporting 

problems. Virtually all of the studies lacked reports of blinding among subjects (n=73), persons 

measuring MPA (n=74), and outcomes assessors (n=75). Differential losses to followup were 

not reported in 61 studies. The authors of only 29 studies made an attempt to control for 

confounding. Some aspects of reporting were good, though, as the authors of most of the 

observational studies described the methods used to measure MPA (n=68) and clearly defined 

their outcomes (n=69). 

Discussion

What is the Evidence That Monitoring Mycophenolic Acid in Patients 

who Receive a Solid Organ Transplant Results in a Lower Incidence 

of Transplant Rejections and Adverse Events Compared to Patients 

who are not Monitored? 

Three studies (four reports)7-10 directly addressed this question, although the first study was 

not designed to compare monitoring versus no monitoring and the second study9

 found no 

evidence to suggest that monitored patients had a lower incidence of transplant rejections relative 

to non-monitored patients. The third study,10 the first published RCT to compare monitoring 

versus no monitoring of MPA in any patient group, found a lower incidence of treatment failures 

in the monitored group. However, the RCT is limited to adult kidney transplant patients, so the 

efficacy of monitoring in other patient populations is still unknown. Likewise, the clinical 

applicability of the trial’s limited AUC sampling strategy, or the applicability of the 40 mg*h/L 

MPA target dose, to these other populations is also unknown. 

Does the Incidence Differ by MPA Dose and Dose Frequency?

The evidence to support an association between MMF dosage and rejection is inconclusive. 

Most studies were not designed to directly assess whether there was an association between 
6

MMF dosage and rejection or adverse events. Solid clinical recommendations can only be made 

after further research is conducted, preferably using RCTs to compare different fixed doses and 

different targets for concentration control. 

Does the Incidence Differ by Type of MPA? 

None of the included studies directly compared ECMPS with MMF, so this question could 

not be answered. 

Does the Incidence Differ by Total Versus Free MPA, Albumin, Genetic 

Differences, Metabolites? 

None of the included studies confirmed the hypothesis that measurements of free MPA 

correlate better with outcomes than total MPA, although free (not total) MPA was found to be 

associated with infections and haematological adverse events in three studies.13,14,17

One pharmacogenetic study79 showed that carriers of the two multidrug resistance protein 

(MRP2) single nucleotide polymorphisms (SNP) were protected from reduced MPA exposure in 

mild liver dysfunction. A second genetic study found associations between MPA and genes, 

genes and diarrhea, and MPA and rejection. The clinical relevance of both studies to MPA 

monitoring is unclear. 

The studies regarding metabolites yielded few positive results.15,16 Larger, randomized trials 

are necessary to establish the utility of monitoring MPA and its metabolites. 

Does the Incidence Differ by Assay Method?

In two studies,26,27 HPLC and EMIT performed similarly well in the assessment of acute 

rejection risk in pediatric kidney transplant patients. EMIT cut off values were higher than those 

derived from HPLC measurements. The study populations were pediatric patients, and it 

remains to be seen whether diagnostic sensitivities and specificities between HPLC and EMIT 

would differ in other populations. 

Does the Incidence Differ by Analytical Method of MPA Monitoring?

There was no evidence to directly answer this key question. 

Does the Evidence Differ by Age, Gender, Ethnicity, Concomitant Use 

of Calcineurin Inhibitors or Other Medications, or Comorbidity? 

The evidence from the literature failed to directly address the key question. Of the studies 

that were included in the report, the focus was on adults and kidney transplant recipients. Few 

studies involved children or other solid organ transplants. Also, study findings were difficult to 

compare because measures of MPA in the serum or plasma sometimes exhibit large intra- and 

inter-patient variability over time post transplant. 
7

What is the Short- and Long-Term Cost-Effectiveness of Avoiding 

Acute Rejection Due to MPA Monitoring? 

The published literature contains no data on the cost-effectiveness of monitoring versus no 

monitoring in solid organ transplants. Therefore, it is not possible to answer this key question. 

Limitations of this Evidence Report

Only English-language, published studies were included in this report, thereby introducing 

the possibility of publication bias. Virtually all of the included studies involved MMF rather 

than ECMPS. Therefore, the conclusions may not be applicable to the enteric-coated 

formulation. 

Conclusions 

The state of knowledge about therapeutic drug monitoring of MPA in solid organ transplants 

is still in its infancy. This is especially so for organs other than the kidney because the 

overwhelming majority of published studies involve kidney transplant patients. Overall, the 

published evidence on MPA monitoring is inconclusive; there is almost no direct evidence to 

suggest that monitoring would reduce the incidence of rejection or adverse events in any solid 

organ transplant. Each of the key questions in this report would be more adequately addressed 

using RCTs. 

Clinical recommendations. There is almost no direct evidence to suggest that monitoring is 

more or less beneficial than not monitoring. Until there is more evidence on the utility of routine 

MPA monitoring in solid organ transplant recipients, patients, clinicians, and other stakeholders 

(e.g., public and private insurers) will have to decide on a case by case basis whether the possible 

but uncertain benefits are worth the extra time and expense of monitoring. 
Evidence Report
11

Chapter 1. Introduction 

Mycophenolic Acid 

Mycophenolic acid (MPA) is an immunosuppressant drug used to prevent rejection of solid 

organ transplants. MPA reversibly inhibits inosine monophosphate dehydrogenase (IMPDH), 

the rate limiting step in the biosynthesis of guanine nucleotides. The drug is marketed as the 

ester prodrug mycophenolate mofetil (CellCept®) for kidney, liver, and heart transplants or 

enteric-coated mycophenolate sodium (Myfortic®) (ECMPS) for kidney transplants. The 

chemical formula is C17H201O6 and the structural formula is shown in Figure 1. The molecular 

mass is 320.34 g.mol-1. 

Figure 1. Structural Formula for Mycophenolate Acid 

Mycophenolate mofetil comes in capsule (250 mg), tablet (500 mg), powder (200 mg/mL 

constituted), and intravenous (500 mg) formulations. ECMPS comes in delayed release tablets 

(180 mg or 360 mg). Recommended dosage regimens for adults on mycophenolate mofetil are 1 

g orally twice daily for kidney transplant recipients, 1 g twice daily intravenously or 1.5 g twice 

daily orally for liver transplant recipients, and 1.5 g intravenously or orally for cardiac transplant 

recipients. Recommended dosages for adult kidney transplant recipients on ECMPS are 720 mg 

twice daily. In pediatric patients, recommended dosages for MMF are 600 mg/m2 administered 

orally twice daily (maximum 2 g or 10 mL daily), while children with a body surface area of 

1.25 to 1.5 m2

 are recommended to get 750 mg twice daily. Children with a body surface area 

greater than 1.5 m2 are recommended to receive 1g twice daily.80 Although Tacrolimus has 

replaced Cyclosporin A as calcineurin inhibitor comedication to a large degree, MPA was 

originally approved by the U.S. Food and Drug Administration only for combination with 

Cyclosporin. The recommended doses refer to this combination. 

The pro-drug Mycophenolate mofetil is rapidly hydrolyzed to MPA by esterases in the gut, 

blood, liver, and kidney. ECMPS does not get hydrolyzed; it is essentially MPA in salt form. 

Oral bioavailability of MPA is between 81 and 94 percent after ingestion of mycophenolate 

mofetil and 72 percent after ingestion of ECMPS. Differences in bioavailability may be due to 

the fact that studies of mycophenolate mofetil were conducted on healthy volunteers while 

studies of ECMPS (e.g., Arns et al.81) were conducted on kidney transplant patients. MPA is 

metabolized in the liver, gastrointestinal tract, and kidney. The major metabolite, 7-O-MPAglucuronide (MPAG), is inactive, and occurs in 20 to 100-fold higher concentrations than 
12

MPA.80 The minor acyl glucuronide metabolite AcMPAG is immunosuppressive and 

proinflammatory. Enterohepatic recirculation of MPA involves excretion of MPAG into bile 

followed by deconjugation to MPA in the gut and reabsorption into the circulation. This effect 

accounts for 10 to 60 percent of MPA exposure and may lead to a second peak in the MPA 

concentration 6 to 12 hours after dosing. Readers interested in further information on the 

pharmacodynamics and pharmacokinetics of MPA are referred to reviews by Staatz and Tett80

and Bullingham et al.82

Solid Organ Transplant 

Solid organs include the kidneys, liver, heart, lungs, pancreas, and intestines. In 2005, there 

were 25,737 solid organ transplants in the United States alone.83 These transplants are used to 

treat end stage organ failure. One year graft survival rates range from 82.0 to 95.0 percent, due 

in large part to refined surgical techniques and the development of effective immunosuppressant 

drugs. The success of solid organ transplants has led to a situation where demand for organs far 

outstrips supply. In mid-2005, over 90,000 Americans were on waiting lists for solid organ 

transplants.84

Mycophenolic Acid: Use in Solid Organ Transplants 

Mycophenolate mofetil. The use of mycophenolate mofetil in solid organ transplants is 

based on the results of five seminal, randomized controlled trials of kidney,85-87 liver,88 and 

cardiac transplant recipients.89 In four trials, patients were randomized to receive mycophenolate 

mofetil or azathioprine in combination with cyclosporine and corticosteroids; one kidney trial85

involved mycophenolate mofetil and a placebo comparison. The average duration of the trials 

was six to 12 months post transplant. Some data are available for 36 months post transplant.90-92 

For the three kidney trials,85-87 a total of 1,493 patients were randomized to treatment. 

Results showed benefits for 2 and 3 g daily doses of mycophenolate mofetil (MMF2, MMF3) at 

six months; however, benefits diminished or disappeared at 12 months and beyond. The 

percentage of patients with biopsy proven rejection in the placebo comparison trial85 at six 

months was 17.0 percent in the MMF2 group, 13.8 percent in the MMF3 group, and 46.4 percent 

in the placebo group (p≤0.001). At 36 months, the difference in graft loss rates for intent-to-treat 

comparisons versus placebo were 7.3 percent (95 percent confidence interval [CI]: 1.1 to 14.2; 

p<0.05) for MMF2 and 3.2 percent (95 percent CI: -3.8 to 10.1; p>0.05) for MMF3.90 In the two 

kidney trials where mycophenolate mofetil was compared to azathioprine, the primary outcome 

at six months was ‘treatment failure’ (any one of the following: biopsy proven rejection, graft 

loss, death, withdrawal for any reason). The percentage of patients with treatment failure in one 

study,86 based in the United States, was 31.1 percent in the MMF2 group, 31.3 percent in the 

MMF3 group, and 47.6 percent in the azathioprine group (p=0.021). Percentages in the other 

study,87 a multinational effort, were 38.2 percent for MMF2, 34.8 percent for MMF3, and 50.0 

percent for azathioprine (p<0.03). The percentages of patients suffering graft loss or death at 12 

months in the multinational study were 11.7 percent in the MMF2 group, 11.0 percent in the 

MMF3 group, and 13.6 percent in the azathioprine group (p>0.05). The investigators in the 

multinational trial reported intent to treat results at 36 months: graft and survival for patients 

receiving MMF2 was 81.9 percent, MMF3 was 84.8 percent, and azathioprine was 80.2 percent 

(p>0.05).91
13

In the liver study,88 565 patients were randomized to treatment and results favored 

mycophenolate mofetil after six months of followup. However, there was no difference between 

mycophenolate mofetil and azathioprine after one year of followup. Percentages of acute 

rejections and graft losses at six months were 38.5 percent in the mycophenolate mofetil group 

and 47.7 percent in the azathioprine group (p<0.03). At 12 months, percentages were 31.0 

percent and 40.0 percent respectively (p<0.06). Graft survival at 12 months was 85.3 percent the 

mycophenolate mofetil group and 85.4 percent in the azathioprine group (p>0.05). 

In the heart study,89 primary results were reported for 578 ‘treated’ patients who received the 

study medication to which they were randomized. A further 72 randomized patients withdrew 

from the study before initiation of treatment. At six months, 65.7 percent of mycophenolate 

mofetil and 73.7 percent of azathioprine patients required treatment for rejection (p=0.026). 

Mortality at 12 months was 6.2 percent in the mycophenolate mofetil group and 11.4 percent in 

the azathioprine group (p=0.031). At 36 months, 11.8 percent of the mycophenolate mofetil 

group and 18.3 percent of the azathioprine group died or received another transplant (p<0.01).92

Enteric-coated mycophenolate sodium. ECMPS was shown to be therapeutically 

equivalent to mycophenolate mofetil in two trials that were initially reported in a single 

publication.1

 Trial 1 contained 424 de novo kidney transplant patients and trial 2 contained 324 

stable maintenance kidney transplant patients who were alive at six months post transplant. In 

trial 1, patients were randomized to 720 mg of oral ECMPS and placebo twice daily, or to 1,000 

mg of oral mycophenolate mofetil and placebo twice daily. Placebos were disguised to look like 

the active drug being given in the opposing treatment arm. The primary outcome was ‘treatment 

failure’ (any one of the following: biopsy proven acute rejection, graft loss, death, or loss to 

followup within six months). After six months, 25.8 percent of patients in the ECMPS group 

and 26.2 percent in the mycophenolate mofetil group experienced a treatment failure (p>0.05). 

Failure results93 at 12 months were 26.3 percent (ECMPS) and 28.1 percent (MMF) (p>0.05). 

Trial 2 patients were randomized to 720 mg of oral ECMPS daily or to 1,000 mg of oral MMF 

daily. The primary outcome was the incidence of gastrointestinal adverse events or neutropenia 

(less than 1,500 cells per mm3

). At three months, there was no difference in incidence of 

gastrointestinal adverse events (26 percent in the ECMPS group; 21 percent in the MMF group 

[p>0.05]). Nor was there a difference at six months (29 percent ECMPS; 28 percent MMF 

[p>0.05]). The authors reported the incidence of neutropenia after three months to be lower in 

patients receiving ECMPS (0.6 percent) versus patients receiving MMF (3.1 percent [p>0.05]). 

Neutropenia results were unchanged after 12 months of followup.94 Concomitant therapies in 

both trials included cyclosporine with or without corticosteroids. 

ECMPS and MMF were also compared in a single blind trial of 154 de novo heart transplant 

patients.95 Results showed therapeutic equivalence between drugs. Patients were randomized to 

1,080 mg ECMPS twice daily or to 1,500 mg MMF twice daily. ‘Treatment failure’ (biopsy 

proven and treated acute rejection, graft loss, or death) was the outcome. The percentage of 

patients having the outcome did not differ (p>0.05) between groups at six or 12 months of 

followup: 52.6 percent versus 57.9 percent at six months and 57.7 percent versus 60.5 percent at 

12 months. 

Adverse events. Common adverse events of MPA include gastrointestinal upset (nausea, 

vomiting, mild diarrhea), headache, mild weakness, dizziness or tremor, insomnia, and swelling 

of the lower legs or feet. There is also an increased risk of lymphoma or other cancers.96

In clinical trials, patients taking mycophenolate mofetil had more abdominal pain, diarrhea, 

esophagitis, anorexia, gastrointestinal bleeding, leucopenia, anemia, and opportunistic infections 
14

(e.g., cytomegalovirus [CMV], herpes simplex or zoster) than patients taking placebo or 

azathioprine. Patients taking 3 g MMF daily generally had more adverse events than patients 

taking 2 g MMF daily. There were no differences in the incidence of cancers between any of the 

treatment groups.85-89 In trials where mycophenolate mofetil was compared to ECMPS,1,93,94

adverse events were generally higher in the MMF group, although the differences were not 

statistically significant at the 5 percent level. The incidence of gastrointestinal adverse events 

was higher in the ECMPS group (29.6 percent versus 24.5 percent),94 although the difference 

was also not statistically significant. The incidence of cancer did not differ between treatments. 

Therapeutic Drug Monitoring of Mycophenolic Acid 

Therapeutic drug monitoring (TDM) is the measurement and subsequent interpretation of drug 

concentrations in biological fluid. Drugs exhibiting the following characteristics may warrant 

TDM: a good relationship between concentration and pharmacological response; wide 

interpatient variation in absorption, distribution, metabolism, or excretion; a narrow therapeutic 

range; and a pharmacological response that is not readily assessable. TDM may be useful for 

monitoring adherence, identifying drug interactions, and tailoring doses to specific patients.97

TDM has become central to the use of immunosuppressants. The aim is to improve control 

over acute rejection and boost the probability of long term patient and graft survival.98 TDM of 

MPA is based on observed associations between total MPA area under the concentration-time 

curve (AUC0–12 h) and acute rejection in adult and pediatric patients.11,17,42,99 However, this 

evidence is viewed by some as equivocal.2,3 

Additionally, there are numerous challenges that must be addressed as a prerequisite for 

TDM of MPA. Most notable is the impracticality of repeated 12 hour measures of AUC in 

standard practice settings. There have been suggestions of methods to overcome the 

impracticality of total AUC (e.g., use of limited sampling strategies4

 or Bayesian estimation2), 

but none of these possibilities has been thoroughly investigated to date. 

Other challenges include the difficulty of using existing, routine assays to quantitate free 

MPA, which is thought to be the prime driver of MPA’s immunosuppressive effect, as well as 

the need to establish and validate effective therapeutic ranges for TDM.4 Some researchers3 do 

not believe that free MPA has much of a role in TDM because its correlation with clinical 

outcomes is not improved over the correlation between total MPA and clinical outcomes. 

Recently Roche has introduced an IMPDH based assay for free and total MPA. A CEDIA assay 

is now available from Microgenics. 

Improved prophylaxis with multiple drugs has lowered the rejection risk. This makes 

additional improvements based on dosing of one drug and definition of a lower limit of the 

therapeutic range challenging. 

Further issues in TDM of MPA include wide intra patient variability in MPA plasma 

concentration-time profiles, non-linear pharmacokinetics, increase of MPA exposure with time 

early after kidney transplantation, no established frequency and duration of monitoring, 

uncertainty about the extent to which baseline IMPDH may contribute to pharmacodynamic 

differences in persons receiving MPA, problematic bioavailability in renally impaired patients, 

and no agreement on a pharmacokinetic (PK) parameter that would best associate with adverse 

events.4

 Some6 believe the occurrence of gastrointestinal adverse events may be associated with 

dose rather than a pharmacokinetic variable. Adverse events are relatively rare, not specific to 
15

MPA, and thus difficult to assess objectively. An upper limit of a therapeutic range is therefore 

difficult to determine. 

Scope and Purpose of the Evidence Report 

This evidence report was designed and conducted to address the following key questions: 

1. What is the evidence that monitoring mycophenolic acid in patients who receive a solid organ 

transplant results in a lower incidence of transplant rejections and adverse events compared to 

patients who are not monitored? 

2. Does the incidence differ by any of the following? 

a) MPA dose and dose frequency;

b) Type of MPA (mycophenolate mofetil [CellCept®], enteric-coated mycophenolate sodium 

[Myfortic®]).

3. a) Does the incidence differ by any of the following?

ia. Total versus free MPA 

ib. Albumin versus MPA 

iia) MPAG, AcMPAG versus MPA 

iib) Genetic basis of differences in MPA pharmacokinetic parameters 

iii) Assay method (EMIT, HPLC, HPLC-MS, other) 

 b) Does the incidence differ by analytical method of MPA monitoring?

i. Full AUC (area under the curve) 

ii. Limited sampling strategies 

a. Predose concentrations 

b. 2h post dose concentrations 

c. Other 

 

4. Does the evidence for monitoring MPA differ by any of the following?

a) Age 

b) Gender 

c) Ethnicity 

d) Concomitant use of calcineurin inhibitors (e.g., tacrolimus, cyclosporine) 

e) Concomitant use of other medications 

f) Comorbidity 

5. What is the short and long-term cost-effectiveness of avoiding acute rejection due to MPA 

monitoring? 

Addressing these questions will help to gauge the strength of the evidence for TDM of MPA in 

solid organ transplants. As well, the exercise will identify gaps in the research and provide 

suggestions for future research. 
17

Chapter 2. Methods 

Analytic Framework 

An analytic framework is a schematic representation of the strategy for organizing topics for 

review and guiding literature searches. Figure 2 illustrates the inter relationships between the 

key questions for this evidence report. The figure begins with the use of CellCept® or Myfortic®

in solid organ transplant recipients, progresses to monitoring MPA (mycophenolic acid) 

concentrations in serum or plasma, and concludes with an outcome (e.g., rejection or adverse 

events). Throughout the entire diagram, each box is suggestive of an area where resources are 

consumed. The cost of these resources may be computed using standard health economics 

methods and compared to an outcome (e.g., life years gained, quality adjusted life years gained) 

to obtain incremental cost effectiveness ratios.100

Within the ‘monitoring’ subsection of the framework, the issues to consider are the form and 

method of MPA monitoring. In our analysis of form, we also include the type of MPA (total 

[bound and free], free) and the means for measuring each type in serum or plasma, namely 

assays such as HPLC (High-Performance Liquid Chromatography), HPLC-MS (HighPerformance Liquid Chromatography-Mass Spectrometry), or EMIT (Enzyme-Multiplied 

Immunoassay Technique). In our analysis of form, we also include variations in albumin (to 

which MPA binds strongly), concentrations of MPA metabolites, and pharmacogenetics. 

Methods of monitoring include total AUC0–12 (area under the curve) and limited sampling 

strategies such as two hour (2h) post dose concentrations and predose concentrations. 

Several factors are hypothesized to affect the utility of MPA monitoring, including age, 

gender, ethnicity, use of calcineurin inhibitors or concomitant medications, and comorbidity. 

This is because these factors may influence the disposition of MPA (i.e., adsorption, distribution, 

metabolism, or excretion). 

Topic Assessment and Refinement 

Research Team 

The McMaster University Evidence-based Practice Center (MU-EPC) assembled a 

multidisciplinary research team with expertise in epidemiology and systematic reviews (M. 

Oremus, Ph.D.; P. Raina, Ph.D.), toxicology (J. Zeidler, Ph.D.), clinical chemistry (C. Balion, 

Ph.D.), pediatric nephrology (M. Matsuda-Abedini, M.D.), and pharmacy (M. Ensom, 

Pharm.D.). The team was tasked with planning an approach to completing this evidence report 

in a thorough, timely, and efficient manner. The team had regular meetings in the initial stages 

of the project to reach consensus on key methodological issues. The team was also responsible 

for supervising the literature search, screening, and data abstraction. The team synthesized the 

literature and wrote the discussion. 

The research team held a ‘kick-off’ teleconference with representatives from the partner 

organization (American Association of Clinical Chemistry), the Agency for Healthcare Research 

and Quality (AHRQ), and MU-EPC staff at the start of the project to define the magnitude of the 
18

topic and refine and clarify the preliminary key questions. A Technical Expert Panel (TEP), 

composed of internationally recognized experts in MPA, was assembled to provide high level 

content expertise on MPA monitoring. Members of the TEP were requested to participate in 

teleconferences on an as needed basis throughout all phases of the project. 

Technical Expert Panel Teleconference Calls 

The first TEP teleconference call took place on February 8, 2007. Technical experts included 

Dr. Klemens Budde (Managing Senior Physician, University Clinic Charité), Dr. Guido Filler 

(Chair/Chief, Department of Pediatrics, Children’s Hospital of Western Ontario), Dr. Atholl 

Johnston (Professor of Clinical Pharmacology, Barts and the London, Queen Mary's School of 

Medicine and Dentistry), and Dr. Leslie M. Shaw (Professor of Pathology and Laboratory 

Medicine, Hospital of the University of Pennsylvania) (see Appendix E∗

 for a list of TEP 

members). A second TEP teleconference took place on April 18, 2007 (Drs. Budde, Filler, 

Johnston, and Shaw present). Several topics were discussed during both calls, including the 

definition and scope of the key questions, search strategies, inclusion and exclusion criteria, and 

the composition of the screening and data abstraction forms. 

 

∗ Appendixes and Evidence Tables for this report are provided electronically at http://www.ahrq.gov/clinic/tp/mpaorgtp.htm
19

Figure 2. Analytical Framework 

Solid organ transplant (kidney, lung, heart, liver, intestine, pancreas) 

Mycophenolic Acid (dosage form and frequency) 

Monitoring MPA 

Factors affecting the monitoring of MPA 

Adverse events (e.g., gastrointestinal, hematologic, other) 

Methods of monitoring 

AUC Limited sampling 

strategies 

Predose concentrations 

2h post dose 

concentrations 

Other 

CellCept® Myfortic®

Assay method Free vs. total MPA, Albumin vs. MPA 

Other 

EMIT 

HPLC-MS 

HPLC 

Biological markers 

Metabolites Genotype 
20

General Methods 

Key Questions 

The original set of key questions for this evidence report was revised by the MU-EPC 

research team and discussed during the TEP teleconferences. Additional discussants at the 

teleconferences included representatives from the partner organization and the AHRQ’s Task 

Order Officer (TOO). 

The revised key questions are: 

1. What is the evidence that monitoring mycophenolic acid in patients who receive a solid organ 

transplant results in a lower incidence of transplant rejections and adverse events compared to 

patients who are not monitored? 

2. Does the incidence differ by any of the following? 

a) MPA dose and dose frequency;

b) Type of MPA (mycophenolate mofetil [CellCept®], enteric-coated mycophenolate sodium 

[Myfortic®]). 

3. a) Does the incidence differ by any of the following?

ia) Total versus free MPA 

ib) Albumin versus MPA 

iia) MPAG, AcMPAG versus MPA 

iib) Genetic basis of differences in MPA pharmacokinetic parameters 

iii) Assay method (HPLC, EMIT, HPLC-MS, other) 

 b) Does the incidence differ by analytical method of MPA monitoring?

i. Full AUC 

ii. Limited sampling strategies 

a. Predose concentrations 

b. 2h post dose concentrations 

c. Other 

4. Does the evidence for monitoring MPA differ by any of the following?

a) Age 

b) Gender 

c) Ethnicity 

d) Concomitant use of calcineurin inhibitors (e.g., tacrolimus, cyclosporine) 

e) Concomitant use of other medications 

f) Comorbidity 

5. What is the short- and long-term cost-effectiveness of avoiding acute rejection due to MPA 

monitoring? 

Literature Search Strategy 

We conducted a comprehensive search of the literature to capture all relevant, published 

studies on the topic of therapeutic drug monitoring (TDM) for MPA. The following electronic 

databases were searched: 

1. MEDLINE® (1966- October 22, 2007); 

2. BIOSIS® Previews (1976- October 22, 2007); 

3. EMBASE® (1980- October 22, 2007); 
21

4. Cochrane Database of Systematic Reviews® (1995- October 22, 2007); 

5. Cochrane Central Register of Controlled Trials® (1995- October 22, 2007). 

Appendix A∗

 contains a detailed description of the database search strategies. 

To supplement the database search, we examined the reference lists of several recently 

published review articles3-6 and consulted with the TEP to identify additional published studies. 

Inclusion/exclusion criteria. We included studies published in the English language, 

provided they were randomized controlled trials (RCTs), observational studies with comparison 

groups (e.g., cohort, case control), or case series (a retrospective or prospective study with a 

single group of subjects [no comparison group] enrolled according to predefined criteria). Case 

reports, narrative and systematic reviews, editorials, comments, letters, opinion pieces, abstracts, 

conference proceedings, and animal experiments were excluded from the report. We included 

studies of pediatric and adult patients who received allograft solid organ transplants from live or 

deceased donors, provided that any form of MPA was measured in serum or plasma. At least 

one measure, at one point in time, had to be made using any method of measurement (e.g., 

AUC). We excluded studies that did not link the measures of MPA in blood to a health outcome. 

Examples of health outcomes included transplant rejection, graft survival, overall patient 

survival, or mortality. Certain biomarkers (e.g., serum creatinine, glomular filtration rate [GFR]) 

and all adverse events were also considered health outcomes. 

Data Collection and Reliability of Study Selection 

A team of trained raters, composed of research assistants, MU-EPC staff, and members of the 

research team, applied the inclusion and exclusion criteria to the citations that were identified in 

the literature search (see Appendix B). A guide and standardized forms were developed to 

govern the screening process. The forms were created and stored online using Systematic 

Review Software v4.0 (SRS; TrialStat Corp., Ottawa, Ontario, Canada). 

The screening process was divided into two levels: title and abstract, and full text. For title 

and abstract screening, two independent raters evaluated the citations that were obtained from the 

literature search. Citations that met the inclusion criteria or for which there was insufficient 

information to determine whether or not they did, were retrieved for further assessment. Once 

retrieved, the entire study publication (full text) was screened to determine if the inclusion 

criteria were met. At this stage, the raters assigned the included studies to categories based on 

the key question or questions to which the studies applied. Inclusion of studies required 

agreement from both raters. Discrepancies were resolved by consensus. If consensus could not 

be reached, then a third party arbitrator reviewed the study in question and made a final decision. 

The arbitrator was an epidemiology trained member of the MU-EPC staff who was not otherwise 

involved in the screening process. 

Studies that passed the full text screening phase proceeded to full data abstraction. Data were 

abstracted by MU-EPC staff (including two trained physicians). Members of the research team 

who were responsible for synthesizing data for the key questions reviewed the abstractions to 

confirm the accuracy of the work. 

 

∗ Appendixes and Evidence Tables for this report are provided electronically at http://www.ahrq.gov/clinic/tp/mpaorgtp.htm
22

Quality Assessment of Included Studies 

The methodological quality of included studies was assessed using ‘core’ criteria enumerated 

in the draft Evidence-based Practice Center Methods Manual (under preparation by the AHRQ). 

These core criteria represent the most important elements by which to judge study quality.101,102 

The criteria were formulated into questions, which are shown in Appendix B∗. Two reviewers 

independently assessed study quality and resolved discrepancies by consensus. 

For controlled trials, we examined the following topics: method of randomization, method of 

allocation concealment, baseline comparison of groups, differences between groups at baseline, 

availability of intent to treat analysis, description of methods used to measure MPA, definition of 

the outcomes related to monitoring MPA, blinding of subjects, persons measuring MPA, persons 

assessing outcomes and the presence of a differential loss to followup between groups. 

For observational studies, we examined the following topics: sample size for primary and 

secondary outcomes, selection method of subjects, baseline comparison of groups, differences 

between groups at baseline, description of the methods used to measure MPA, definition of 

outcomes related to monitoring MPA, blinding of subjects, persons measuring MPA, persons 

assessing outcomes, presence of a differential loss to followup between groups and whether the 

authors controlled for confounding. 

Summary of Findings: Descriptive and Analytic Approaches 

A qualitative descriptive approach was used to summarize study characteristics and 

outcomes. Multiple reports on the same study cohort were grouped together and treated as a 

single study with the most current data reported for presentation of summary results. 

Descriptive approaches were used to summarize the characteristics of included studies and 

answer the key questions. The research team judged that a meta-analysis was not feasible 

because the included studies contained far too much clinical and methodological heterogeneity. 

Instead, data were collected during the abstraction on the characteristics of study participants, 

treatment regimen, form of MPA, method of measuring MPA, measurement time points, and 

outcomes. The quality of this information was judged and the findings were summarized in both 

text and tables. This evidence report provides a greater understanding of TDM for MPA, 

identifies gaps in existing research, and suggests future research. 

Peer Review Process 

The partner organization, TOO, research team, and members of the TEP identified potential peer 

reviewers. The MU-EPC compiled a list of these reviewers, all of whom were approved by the 

AHRQ prior to the circulation of the draft report. The reviewers were asked to review the report 

and provide feedback on clinical and methodological content, as well as on the readability and 

presentation of information. Their comments and suggestions were incorporated where possible. 

 

∗ Appendixes and Evidence Tables for this report are provided electronically at http://www.ahrq.gov/clinic/tp/mpaorgtp.htm
23

Chapter 3. Results 

Literature Review and Screening 

The literature search yielded 11,642 citations. In total, 1,147 citations (96 percent) were 

excluded from further review following initial title and abstract screening; 495 citations 

proceeded to full text screening. Of these 495 citations, 406 (82 percent) were excluded from 

further review and 89 (18 percent) advanced to the data abstraction phase. At this phase, the 89 

studies were slotted according to the key question or questions to which they applied. Three 

studies103-105 were not relevant for any of the review questions. Figure 3 depicts the flow of 

studies through the screening process. As well, the figure shows the reasons for study exclusion. 

The remainder of this chapter contains sections describing the evidence for the key questions and 

a quality assessment of the studies. 

Key Questions 

Question 1. What is the Evidence That Monitoring Mycophenolic Acid 

in Patients who Receive a Solid Organ Transplant Results in a Lower 

Incidence of Transplant Rejections and Adverse events Compared to 

Patients who are not Monitored? 

Only three studies (four reports)7-10 contained one group of patients who were monitored and 

one group of patients who were not monitored. The first study was published by Meiser et al. in 

two companion papers with identical results.7,8 The investigators consecutively enrolled 15 

adult, orthotopic heart transplant patients into a study of fixed dose MMF (Mycophenolate 

Mofetil) (2 g daily) and tacrolimus (group 1). A further 30 patients with the same characteristics 

were subsequently enrolled to receive MMF and tacrolimus, with MMF dose adjusted according 

to plasma predose concentration (group 2). Target plasma predose concentrations were set 

within a range of 2.5 to 4.5 μg/mL. Mean lengths of followup were 696 days (group 1) and 436 

days (group 2). Five group 1 patients remained rejection free over the course of followup; 27 

group 2 patients also remained rejection free. Plasma MPA (Mycophenolic Acid) predose 

concentrations were measured retrospectively in group 1 patients and an inverse association was 

found between mean plasma MPA and the number of rejection episodes per patient: 0 rejections 

(3.6 μg/mL); one to two rejections (2.2 μg/mL); three rejections (1.4 μg/mL). For group 2 

patients, the authors report only the MPA plasma concentrations for the three patients who 

suffered rejection (1 rejection episode per patient): 0.7, 1.3, and 0.9 μg/mL. Diarrhea or 

vomiting were reported in six group 1 patients and nine group 2 patients; cytomegalovirus 

(CMV) was reported in three group 1 patients and four group 2 patients. The authors do not 

provide p-values or confidence intervals for any inter or intra-group comparisons. 

Flechner et al.9

 conducted a similar sequential allocation study by recruiting one group 

(n=160) of kidney transplant recipients who received a fixed dose of 2 g MMF daily and a 

starting dose of 5 g p.o. sirolimus. After this group was recruited, the investigators recruited 

another group (n=100) who received 1 g MMF daily (sirolimus regimen unchanged relative to 
24

2 g group). Dosage in the 1 g group was adjusted to keep MPA C0 concentrations between 1.8 

and 4.0 μg/mL. 

After six months of followup, there were no differences (p>0.05) between groups in biopsy 

confirmed acute rejections (8.8 percent [2 g] versus 13.0 percent [1 g]) or mean serum creatinine 

concentrations (1.41 mg/dL [2 g] versus 1.47 mg/dL [1 g]). There were also no differences in 

the incidence of CMV or Polyoma viral infections. However, the incidence of some 

gastrointestinal adverse events was lower in the 1 g group: nausea, vomiting, or dyspepsia (8.0 

percent versus 20.6 percent; p=0.007); abdominal pain (4.0 percent versus 10.6 percent; p=0.05); 

diarrhea (20.0 percent versus 34.3 percent; p=0.01). 

The third study,10 which was published online in October 2007, was a 12 month RCT 

comparing adult kidney transplant patients in France. Patients received a quadruple 

immunosuppressive regime that included randomization to fixed-dose or concentrationcontrolled MMF. Persons in both groups received 2 g MMF daily for seven days, after which 

the fixed-dose group could receive dose adjustments based on physician experience. In the 

concentration-controlled group, a three-point, limited AUC (area under the curve) sampling 

strategy (20, 60, and 180 minutes post-MMF administration) was calculated using Bayesian 

estimates to achieve an MPA target dose of 40 mg h/L. MPA was measured with the HPLC 

assay at days 7 and 14 post-transplant, as well as at months 1, 3, 6, and 12. The primary 

endpoint was treatment failure, which was a composite endpoint consisting of death, graft loss, 

acute rejection (renal biopsy or Banff classification), or MMF discontinuation. The primary 

analysis was an intent-to-treat analysis consisting of 65 patients in each group. There were more 

treatment failures in the fixed-dose group (n=31; 47.7 percent) than in the concentrationcontrolled group (n=19; 29.2 percent) (p=0.03). The principal component of these failures was 

the difference in any type of acute rejection (fixed-dose: n=20 rejections; concentrationcontrolled: n=8 rejections [p=0.01]). The remaining components of the composite outcome were 

not statistically significantly different at the 5 percent level. Adverse events tended to be higher 

in the concentration-controlled group, although the only statistically significant difference 

(p<0.05) was observed in the case of herpes (eight events in the concentration-controlled group; 

one event in the fixed-dose group). 
25

 

Figure 3. Flow diagram showing the number of citations processed at each level of the screening process 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Full text screen 495

 

 

 

 

 

Title and abstract screen 11,642

Screened for applicability to review questions....89

Question 5: What are the short-term and long-term cost savings of avoiding acute 

rejection due to MPA monitoring...............................................................0 

Question 2b: Does the incidence differ by type of MPA................................... 0 

Question 3a: Does the incidence differ by the form of MPA monitored..................22 

 Question 2a: Does the incidence differ by dose or dose frequency.........................41 

Question 1: What is the evidence that monitoring mycophenolic acid in patients who 

receive a solid organ transplant results in a lower incidence of transplant rejections and 

adverse events compared to patients who are not monitored...................................4 

 Question 4: Does the evidence differ by age, gender, ethnicity, use of calcineurin 

 inhibitors, use of other medications, comorbidity...........................................38 

 Question 3b: Does the incidence differ by method of MPA monitoring.............. .......71

Do not provide data specifically applicable to any of the

review questions.........................................3 

Exclude: Not English language................................................735 

Exclude: Not a full report of a primary study..............................8083 

Exclude: Does not evaluate humans with solid organ transplants........365 

Exclude: Does not measure any form of MPA in blood..................1964

Exclude: Not English language................................................................1 

Exclude: Not a full report of a primary study..............................................57 

Exclude: Does not evaluate humans with solid organ transplants......................21 

Exclude: Does not measure any form of MPA in blood................................166 

Exclude: Health outcomes are not associated with MPA blood concentrations....161 
26

Question 2. Does the Incidence Differ by any of the Following? 

2a: MPA Dose and Dose Frequency 

The association between dosage and incidence of transplant rejections and adverse events has 

been described in 41 articles (38 separate studies) of patients who received a solid organ 

transplant (See Evidence Table 1, Appendix C∗).7,8,11,12,14-16,18,21,22,24,25,27,28,30,31,33,35,36,39-42,44,51-

53,56,59-62,67,69,72,73,75-77,106,107 Of the 41 articles, one7

 was described in a duplicate report,8 two 

others reported on the same study (i.e., study design and patient population) yet contained 

different analyses,11,12 and another study reported with two different analyses.36,52 Five studies 

(six articles) were randomized controlled trials,11,12,25,28,51,75 two (three articles) were non 

randomized controlled trials,7,8,31 seven (one of which was also described in a separate case 

series) were prospective cohort studies,24,35,39-41,52,77 two were case control,53,106 two were 

retrospective cohort studies,22,42 and 20 (one of which was already described in a separate 

prospective cohort study52) were case series.14-16,18,21,27,30,33,36,44,56,59-62,67,69,72,73,76

Most studies were in kidney transplant recipients. Liver transplant recipients were studied 

separately in three studies,40,61,62 with kidney transplant recipients in one study,39 and kidney and 

small bowel transplant recipients in another.24 Heart transplant recipients were studied in five 

studies (six reports).7,8,42,44,45,70 Pediatric transplant recipients were studied separately in two 

studies,27,73 with young adults in one study,44 and adults in one study.40 Of the four pediatric 

studies, two were kidney transplant,27,73 one was liver transplant,40 and one heart transplant.44

Young adults were studied with adults in one kidney transplant study.41 All other studies 

involved persons over 16 years of age. There were no studies comparing dose frequencies. 

The results of the studies for Question 2a are shown in Tables 1 to 4. In the following 

paragraphs, we outline the results of the most important studies that address this issue. A total of 

10 studies11,28,30,31,33,35,36,42,52,53 examined whether MMF dosage was associated with rejection. 

Three studies30,31,35 found an association and seven did not.11,28,33,36,42,52,53 Only one study, an 

RCT by Hale et al.,11 attempted to compare rejection outcomes for subjects with planned dose 

adjustments based on different target MPA plasma or serum concentrations. 

In the Hale et al. trial kidney transplant recipients were allocated to three pre-defined MPA 

AUC groups (low: 16.1 μg h/L; intermediate: 32.2 μg h/L; high: 60.6 μg h/L). The incidence of 

biopsy proven acute rejection was 25.5 percent, 8.5 percent, and 5.8 percent respectively in each 

of the three groups (p=0.043). Univariate logistic regression p-values between biopsy proven 

rejection vs. MPA AUC0-12, MPA Cmax, MPA C0, and MMF dose were < 0.0001, 0.0008, 0.0049, 

and 0.0918, respectively (not significant for MMF dose). In multivariable logistic regression 

analysis, MPA AUC remained statistically significant, but MPA Cmax, MPA C0 (predose plasma 

or serum concentration), and MMF dose were all not significant. 

There were a total of 20 studies containing evidence about whether MMF dosage was 

associated with adverse events. Ten (11 reports) showed statistically significant 

associations11,12,14-16,22,33,62,69,72,75 and 10 showed no significant associations.14,21,31,35,51,53,56,61,72,76 

Positive associations were observed in the RCT conducted by Hale et al.11 and van Gelder et al.12

(two reports using data from the same trial), which was the only study that attempted to compare 

adverse effect outcomes for subjects with planned dose adjustments based on different target 

MPA plasma concentrations (low: 16.1 μg h/L; intermediate: 32.2 μg h/L; high: 60.6 μg h/L). 

 

∗ Appendixes and Evidence Tables for this report are provided electronically at http://www.ahrq.gov/clinic/tp/mpaorgtp.htm
27

The risk of diarrhea and the risk of premature study withdrawal due to adverse events were both 

significantly associated with mean MMF dose.11 Posthoc analysis further showed that only the 

premature withdrawal due to gastrointestinal (and not other) adverse events was significantly 

related to MMF dose. This suggests that high local, non systemic, drug concentrations may be 

responsible for MMF’s gastrointestinal adverse events. A case series conducted by Hubner et 

al.56 in kidney transplant recipients reported adverse events for subjects with planned dose 

adjustments based on MPA predose concentrations and subjects taking MMF without changes 

based on plasma concentrations. The data were graphically depicted and, as such, no direct 

comparisons could be made. However, the data did show that there was no significant difference 

in mean MMF dose between patients with or without adverse events (1.77 g/day versus 1.89 

g/day, p>0.05). 

2b: Type of MPA (mycophenolate mofetil [CellCept®], enteric-coated 

mycophenolate sodium [Myfortic®]) 

There was no evidence in the included studies to answer this question. ECMPS was used in 

only one study,32 which consisted of 12 kidney transplant recipients who were given 720 mg of 

the drug twice daily within 48 hours post transplant. All of the other included studies used 

MMF. No study contained direct comparisons of ECMPS and MMF. 

Question 3a: Does the incidence differ by any of the following? 

Does the Incidence Differ by Albumin versus MPA? 

Twenty two studies included measurements of free MPA or albumin in addition to total MPA 

(See Evidence Table 1, Appendix C∗

).13-21,38,40,52,53,66,69,79,108-113 There were 12 case series,14-

19,21,66,69,110,111,113 six prospective cohort studies,13,20,38,40,52,79 two case control studies,53,112 and 

two non randomized controlled trials.38,108 The transplanted organs were livers in two 

studies,40,66 hearts in one study,19 and kidneys in the remaining 19 studies. Sample sizes ranged 

from eight21,113 to 210.40 Patients were between 0.340 and 77 years old.38 The percentage of 

male study subjects ranged from a low of 38 percent in one study21 to a high of 82 percent in 

another.19 Patients were followed up from one111,113 to 38 months.14 Of these 22 studies, 13 

compared total with free MPA or albumin.13-21,109,110,112,113 Out of these, the eight studies most 

relevant to Question 3aia associated adverse events or rejection with measurements of free vs. 

total MPA13,15-20 or albumin versus total MPA.14 See Table 5. All studies except Maes et al.16

and Shaw et al.20 analyzed rejection outcomes. Rejection of a kidney was biopsy proven 

whenever possible and scored according to Banff criteria in four studies.13-15,17 Kidney rejection 

was not defined by Cattaneo et al.18 Rejection of a heart was determined by endomyocardial 

biopsy according to International Society for Heart and Lung Transplantation criteria.19 Maes et 

al.16 looked at orocecal transit time (OCTT) and oroanal transit time (OAT) as measures of 

motility and intestinal absorption in renal transplant patients with persistent afebrile diarrhea. 

Kidney function tests were analyzed in relation to MPA PK (pharmacokinetic) parameters in six 

studies.13-15,17,18,20

 

∗ Appendixes and Evidence Tables for this report are provided electronically at http://www.ahrq.gov/clinic/tp/mpaorgtp.htm
28

All studies except DeNofrio et al.19 had adverse events as outcomes. Adverse events 

(gastrointestinal, haematological, infectious) were well defined by Borrows et al.,14 Atcheson et 

al.,13 and Weber et al.17 Gastrointestinal and haematological adverse events were well defined 

by Kuypers et al.15 and Cattaneo et al.18 Shaw et al.20 had clear definitions of haematological 

adverse events, but not gastrointestinal adverse events. Albumin in relation to MPA PK 

parameters was analyzed in five studies.13,14,17,18,20 In addition to the eight most relevant studies, 

five studies compared free and total MPA in relation to kidney function tests or albumin, but not 

to adverse events or rejection.21,109,110,112,113

The remaining nine studies were not directly relevant to the key question. Eight studies 

related total, but not free MPA or albumin, to an outcome.40,52,53,66,69,79,108,111 Another study 

related free MPA to albumin and renal function and total MPA to adverse events and rejection.38

Rejection, adverse events, and free versus total MPA. Nine studies associated free MPA 

PK parameters or albumin with adverse events or rejection.13-21 Four of these studies did not 

find statistically significant associations between free MPA parameters and adverse events or 

rejection, nor differences in this respect between free and total MPA.15,19-21 Kuypers et al.15 did 

not find significant associations between free or total MPA C0, Cmax (maximum concentration), 

or AUC values and rejection or adverse events in inter and intra-patient comparisons (data not 

shown by authors; p-values only given as not significant). Free median MPA predose 

concentrations within 19 patients were 27.9 μg/L without anemia and 34.2 μg/L with anemia; 

total MPA predose concentrations were and 2.61 mg/L without and 2.0 mg/L with anemia. 

DeNofrio et al.’s study19 of heart transplant patients found lower AUCs of total MPA and free 

MPA (fMPA) in grade 2/3 rejection versus grade 0 or grade 1 rejection (all results significant 

except the total MPA grade 2/3 versus grade 0 comparison [p<0.08]). However, there were no 

reported differences for free versus total MPA. Two studies found that five20 or four21 patients 

with impaired renal function who developed leukopenia tended to have higher fMPA AUCs than 

patients who did not develop leukopenia, but the small numbers did not allow statistical 

conclusions. No comparison to total MPA was made in these cases. Diarrhea in 10 out of 33 

patients was not associated with high free or total MPA C0 or predose values (data not shown by 

authors).20

Atcheson et al.13 found no association between free or total MPA parameters and rejection, 

gastrointestinal effects, or anemia. On the other hand, the mean fMPA AUC0-6 was significantly 

higher in patients with thrombocytopenia, leucopenia, or infections (1.9 mg h-1 l-1) than in 

patients without these outcomes (1.1 mg h-1 l-1; 95 percent CI for the difference: 0.3 to 1.4; 

p=0.0043). Total MPA AUC0-6 values for these outcomes were not different (p=0.18). Weber et 

al.17 also found that fMPA AUC, but not total MPA AUC, were associated with leukopenia and 

infections. Similarly, Cattaneo et al.18 saw a correlation between the free fraction of MPA (but 

not total MPA) and lower red blood cell and leukocyte counts. Borrows et al.14 did not measure 

fMPA, but correlated hypoalbuminemia and renal impairment, both known to increase fMPA 

(see below), with hemotoxicity. Multivariable analysis showed that higher MPA predose 

concentrations, lower serum albumin, and lower estimated creatinine clearance (eCrCl) were 

independently associated with a higher probability of anemia (relative risk [RR] for 1 mg/L rise 

in median MPA concentration in the 30 days before the event: 1.62; 95 percent CI: 1.24 to 2.12; 

RR for 10 g/L rise in albumin: 0.70; 95 percent CI: 0.40 to 0.87; RR for 10 mL/min rise in eCrCl 

(estimated creatinine clearance): 0.80; 95 percent CI: 0.67 to 0.91; p<0.001 for all). According 

to receiver operating curve (ROC) analysis, an MPA predose concentration of 2.60 mg/L and a 

serum albumin concentration of 29 g/L best discriminated patients with and without anemia. 
29

Maes et al.16 studied patients with unexplained enterocolitis and persistent afebrile diarrhea 

without evidence of infections and found a correlation between oroanal transit time and MPA 

(r=-0.87; p=0.02) or fMPA (r=-0.88; p=0.02), but no difference between MPA and fMPA 

(p>0.05). They hypothesized MPA to be causal in this relationship. None of the studies above 

seemed to have found free MPA PK parameters useful to predict diarrhea or rejection. 

Kidney function, albumin, and free MPA. Studies that related kidney function or albumin 

to free MPA measurements13,15,20,21,38,109,110,112,113 generally found that impaired kidney function 

as well as hypoalbuminemia were associated with increased concentrations or AUCs of fMPA 

and MPAG but not total MPA. Weber et al.112 showed that free, but not total, MPA AUC0-12

values were inversely correlated with GFR (Glomerular Filtration Rate) in 18 children and 10 

adults (r=- 0.57, p < 0.01 at 1 week; r=-0.41, p < 0.05 at 3 weeks after renal transplantation). In 

children (36 observations from weeks 1 and 3 combined), the MPA free fraction was inversely 

correlated with serum albumin (r=-0.54, p<0.01) and GFR (r=-0.60, p<0.001). Forward stepwise 

regression showed that the free fraction of MPA was significantly related to albumin and GFR 

(r2

=0.46). In adults the MPA free fraction was also inversely correlated with GFR (r=-0.70, 

p<0.005), but not with albumin. Conversely, Johnson et al.,111 who did not measure fMPA, 

found by multiple linear regression in 10 kidney transplant patients that creatinine (p=0.01) and 

albumin (p=0.03) predicted total MPA AUC0-12. 

Does the Incidence Differ by Genetic Differences or Metabolite 

Concentrations? 

The relationships between genetic polymorphisms, pharmacokinetics of MPA, and health 

outcomes were examined by two studies.30,79 Twenty three studies reported measurement of the 

major, inactive, phenolic conjugate metabolite mycophenolic acid-7-O-glucuronide (MPAG) 

(See Evidence Table 1, Appendix C∗ and Table 6).15,16,18,20-25,32,38,44,58,64,73,108-115 The active acyl 

glucuronide metabolite of MPA (AcMPAG) was measured in two of the 23 studies.15,16 

Fourteen studies were case series,15,16,18,21,30,32,44,58,64,73,110,111,113,116 six were prospective cohort 

studies,20,23,24,79,109,115 two were non randomized controlled trials,38,108 one was a retrospective 

cohort study,22 one was a case control study,112 and one was a randomized controlled trial.25 

Almost all studies dealt only with kidney transplantation, except for two heart transplant 

studies44,58 and one study including liver, small bowel, and kidney recipients.24 Samples ranged 

from five115,116 to 95 people.79 Ages ranged from 1 month44 to 77 years.38 Between 20115,116 and 

73 percent38,58 of participants were male and were followed up from 2 days115,116 to 3 years.23

Outcomes described in one of the genetic papers79 included diarrhea, leucopenia, and other 

haematological disorders, as well as biopsy proven acute rejection, all in relation to single 

nucleotide polymorphisms (SNPs). Liver dysfunction was also described in relation to MPA PK 

parameters and SNP genotype.79 Delayed graft function and hypoalbuminemia were associated 

with MPA PK parameters. The second genetic study30 associated MPA PK parameters and 

SNPs with acute rejection (classified according to Banff criteria) and diarrhea (undefined) with 

genotype. 

Sixteen out of the 23 studies that measured metabolites compared PK parameters of MPA 

with those of its metabolites in relation to health outcomes.15,16,20-25,38,108,110-115 Out of these 

studies, the seven studies most relevant to questions about biological variation associated adverse 

 

∗ Appendixes and Evidence Tables for this report are provided electronically at http://www.ahrq.gov/clinic/tp/mpaorgtp.htm
30

events or rejection with measurements of MPA versus metabolites.15,16,20,22-25 Adverse events 

were described by five studies15,20,22,23,25 Merkel et al.22 list hemoglobin, elevated transaminases, 

CMV infection, and diarrhea (all undefined) as adverse drug reactions. Kuypers et al.15 reported 

anemia (hemoglobin < 11 g/dL beyond the first month), leukopenia (white cells < 4 x 109/L) and 

other less well defined adverse events. Maes et al.16 reported fecal fat loss and Bunchman23

reported undefined gastrointestinal, haematological, and infectious adverse events. Tsaroucha et 

al.24 described only minor gastrointestinal problems without attempts at correlation to MPA. 

Shaw et al.20 defined leukopenia (whole blood count < 5000), but not gastrointestinal effects. 

Behrend et al.25 did not specify their observed adverse events. A few studies22,25,117 did not 

contain clear definitions of rejections. Others15,16,23 used Banff criteria if biopsy was not 

contraindicated. Shaw et al.20 defined rejection as based mostly on creatinine, but didn’t relate 

this outcome to MPA or metabolites, and neither did Maes et al.16 Renal function tests or 

albumin were evaluated in connection with MPA or metabolites in four of the seven 

studies.15,20,22,25 The seven studies of highest relevance were accompanied by nine studies that 

compared MPA and metabolites related to lab based outcomes, but not to adverse events or 

rejection.21,108-113,115,116

The remaining seven less relevant studies did not compare either MPA to metabolites or 

associate outcomes with metabolites.18,32,38,44,58,64,73 They did relate MPA mostly to rejection 

outcomes. 

Pharmacogenetics. Naesens et al.79 found that seven days after transplantation, renal 

allograft recipients (n=9) without the C-24T SNP of the multidrug resistance associated protein 2 

(MRP2), but with mild liver dysfunction, had lower MPA exposure compared to MRP2 C-24T 

non carriers (n=45) without liver dysfunction. Dose corrected MPA C0 concentrations were 1.9 

± 1.6 versus 3.8 ± 3.2 mg/L·g (p=0.045) in liver disease versus no liver disease. Dose corrected 

MPA AUC0-12 values were 34.1 ± 16.8 versus 81.8 ± 51.0 mg·h/L·g (p=0.0007). MPA exposure 

in carriers of the MRP2 C-24T variant were similar with (n=7) or without (n=34) liver 

dysfunction. In this subgroup, the dose corrected MPA C0 concentrations were 3.4 ± 2.5 versus 

4.0 ± 2.5 mg/L·g (p > 0.05) in liver disease versus no liver disease. Dose corrected MPA AUC0-12

values were 94.4 ± 50.4 versus 79.6 ± 35.4 mg·h/L·g (p=0.0007). The C-3972T variant, in 

linkage disequilibrium with C-24T, led to similar effects. The C-24T SNP was associated with 

higher MPA exposure later after transplantation and with more diarrhea within one year after 

surgery. 

Satoh et al.30 studied the circadian variation of MPA PK, the association between MPA PK 

and acute rejection, and the association of several polymorphisms related to the Clock gene, the 

uridine diphosphoglucuronosyltransferase (UGT) system, cytochrome P450 3A5, and the 

multidrug resistance 1 (MDR1) C3435T variant, with circadian MPA variation and the incidence 

of adverse events and rejection. MPA PK was found to vary with the time of the day (daytime 

AUC > nighttime AUC). MPA PK parameters were lower in patients with acute rejection than 

in those without, and the MDR1 C3435T genotype was associated with a higher incidence of 

diarrhea than in patients with the CC genotype (p=0.049). No direct associations between 

genotype, MPA PK, and outcomes were found. 

Rejection, adverse events, and metabolites versus MPA. Seven studies related adverse 

events or rejection with measurements of MPA versus metabolites.15,16,20,22-25 Significant 

associations were found in two studies.15,16 Kuypers et al.15 reported higher median AcMPAG 

(0.24 versus 0.12 mg/L, p=0.03), MPAG C0 concentrations (62.8 versus 58.3 mg/L, p=0.02), and 

AcMPAG/MPA ratios (0.10 vs. 0.06, p=0.004), but not higher MPA C0 concentrations (2.0 vs. 
31

2.61 mg/L, p>0.05) in patients who experienced anemia compared with times when they did not 

experience anemia (intra-patient comparison, 19 concentrations). The authors also found lower 

median MPAG C0 concentrations (n=10) at times of a leucopenia episode compared to 

concentrations at times of no leukopenia (47.2 versus 60.5 mg/L, p=0.04). With these 

exceptions, inter- and intra-patient comparisons of C0 concentrations, AUCs, or Cmax

concentrations of MPA, fMPA, AcMPAG, and MPAG between the presence or absence of acute 

rejection, diarrhea, leucopenia, and anemia yielded no significant differences. 

Maes et al.16 found a correlation between the amount of fecal fat loss (a measure of fat 

malabsorption with steatorrhea) and MPAG concentrations (r=0.9955, p<0.001), as well as 

AcMPAG concentrations (r=0.90, p=0.015) in five renal allograft recipients with persistent 

afebrile diarrhea. 

Negative results concerning MPA and MPAG concentrations were found in association with 

the following: elevated transaminases, CMV infections, diarrhea, and rejections;22 diarrhea, 

anemia, leucopenia, sepsis, and rejections (no data shown);23 adverse gastrointestinal effects and 

rejection in liver transplant recipients;24 diarrhea;20 and unnamed adverse events and rejection 

(data not shown).25

Kidney function, albumin and metabolites versus MPA. Thirteen studies compared MPA 

and metabolites related to lab based outcomes.15,20-22,25,108-113,115,116 MPAG C0 concentrations or 

AUCs were found in all these studies to significantly increase with decreased kidney function as 

measured by creatinine concentrations or clearance. MPA C0 and AUC results behaved less 

predictably and could either increase, decrease, or not change with kidney function. In a study of 

kidney transplant recipients,109 MPAG C0 and AUC were elevated in renal insufficiency 

compared to preserved renal function (MPAG C0 = 274 ± 114 versus 92.6 ± 36 ug/mL, p<0.001; 

MPAG AUC = 3527 ± 1130 versus 1550 ± 392 μg·h/mL, p < 0.001). In contrast, MPA C0 was 

elevated (2.12 ± 1.4 versus 1.15 ± 0.6 μg/mL, p=0.037), but MPA AUC was not (48.9 ± 19 

versus 47.3 ± 8.8 μg·h/mL, p > 0.05). 

Albumin was correlated to MPA, but not to MPAG.22,111 Multiple linear regression with 

adjustment for covariates found that serum albumin in renal allograft recipients positively 

predicted MPA AUC0-12 (p=0.03), but not MPAG AUC0-12.

111

Does the Incidence Differ by Assay Method? 

Among all the included studies, only two case series26,27 involved direct comparisons of 

different assay methods (See Evidence Table 1, Appendix C∗

). Both case series contained 

children with transplanted kidneys from the same longitudinal research project.17,110,112,118 In one 

study, by Weber et al.,26 50 patients (31 males) were between 3.2 and 16.0 years old. In the 

other study, by Armstrong et al.,27 the authors did not report the age or sex of their subgroup of 

40 patients. Followup was for six months26 or 70 days.27

Both papers reported the EMIT (Enzyme multiplied immunoassay technique) and HPLC 

(High performance liquid chromatography) assays to measure total MPA C0, Cmax, and AUC0-12. 

Weber et al.26 also measured C12 (evening predose) and two abbreviated AUCs. Fifteen of the 

patients in the Weber et al. study had a rejection, 11 of which were biopsy proven (Banff criteria) 

and four of which were diagnosed on the basis of one or more clinical findings (i.e., body 

temperature, graft swelling, tenderness, creatinine 20 percent more than baseline value, oliguria). 

 

∗ Appendixes and Evidence Tables for this report are provided electronically at http://www.ahrq.gov/clinic/tp/mpaorgtp.htm
32

Nine patients in the Armstrong et al. study had acute rejection, which the authors did not 

define.27

Both studies found EMIT and HPLC equally able to discriminate between patients with acute 

rejections during the first 70 days post transplant. This was true for C0 and AUC0-12 in the 

Armstrong et al. study27 and for C0, C12, AUC0-12 and the abbreviated AUC estimate 

AUC0,75min,4h in Weber et al.26 Decision concentrations, below which the risk of acute rejection 

is increased, were higher with EMIT than with HPLC, presumably because of the known cross 

reactivity of the EMIT assay with the active metabolite AcMPAG.119 The cut offs for AUC0-12, 

with a diagnostic sensitivity of 67.7 percent and a diagnostic specificity of 79.4 percent, were 

29.5 mg·h/L for HPLC and 36.1 mg·h/L for EMIT.27 The other study showed AUC0-12 cut offs at 

80 percent sensitivity and 57 percent specificity to be 33.8 mg·h/L (HPLC) and 36.1 mg·h/L 

(EMIT).26 Cut offs for C0 were 1 mg/L (sensitivity 77.8 percent, specificity 64.5 percent, HPLC) 

and 1.3 mg/L (EMIT).27 Weber et al.26 reported a better performance of C12 versus C0 with cut 

offs for C12 of 1.2 (HPLC) and 1.4 mg/L (EMIT) (sensitivity 80 percent, specificity 60 percent). 

Areas under the ROC curves for C0, C12 and AUC0-12 ranged from 0.64 (EMIT, AUC, 95 percent 

confidence interval (CI): 0.45 to 0.84; p=0.04) to 0.70 (HPLC, C12, 95 percent CI: 0.53 to 0.87; 

p=0.01),26 or from 0.71 (EMIT, 95 percent CI: 0.51 to 0.91; p=0.020 [AUC]; 0.53 to 0.89; 

p=0.012 [C0]) to 0.73 (HPLC, AUC, 95 percent CI: 0.53 to 0.94; p=0.012).27 Cmax was not able 

to discriminate rejectors significantly in either study. None of the PK parameters, regardless of 

assay method, were associated with the incidence of adverse events (diarrhea, anemia, 

thrombocytopenia, leukopenia, and several viral, fungal and bacterial infections).26

HPLC-MS was used so rarely that the performance of this assay method could not be 

assessed. 

3b: Does the Incidence Differ by Method of MPA Monitoring (Full AUC 

or Limited Sampling Strategies [i.e., Predose Concentrations, 2 hour 

Post Dose Concentrations, Other])? 

 The association between the method of MPA monitoring and incidence of transplant 

rejections and adverse events has been described in 71 reports (67 separate studies) of patients 

who received a solid organ transplant. The characteristics of these studies are shown in Evidence 

Table 1, Appendix C∗).7,8,10-22,24-77,106,120 Of the 67 studies, one7 was described in a duplicate 

report,8

 another was first described partially120 and then in full,48 two other articles reported on 

the same study (study design and patient population) yet involved different analyses,11,12 and 

another study reported with two different analyses.36,52 Eleven studies (12 articles) were 

RCTs,10-12,25,28,29,34,50,51,65,68,75 four (five articles) were non randomized controlled trials,7,8,31,38,49

nine (one of which was also described in a separate case series) were prospective cohort 

studies,13,20,24,35,39-41,52,77 three were case control,53,54,106 three were retrospective cohort 

studies,22,42,55 and 41 (including one48 that was also published partially120) were case series.14-

19,21,26,27,30,32,33,36,37,43-48,53,54,56-64,66,67,69-74,76,106

Most studies were in kidney transplant recipients. Liver transplant recipients were studied 

separately in six studies,34,40,61,62,66,71 with kidney transplant recipients in one study,39 and with 

kidney and small bowel transplant recipients in one study.24 Heart transplant recipients were 

studied in eight studies, (nine reports).7,8,19,42,44,45,55,58,121 Pediatric transplant recipients were 

 

∗ Appendixes and Evidence Tables for this report are provided electronically at http://www.ahrq.gov/clinic/tp/mpaorgtp.htm
33

studied separately in seven studies,17,26,27,46,55,63,73 with young adults in one study,44 and with 

adults in one study.40 Of the nine pediatric studies, all involved kidney transplant with the 

exception of one in liver transplant40 and two in heart transplant.44,55 Young adults were studied 

with adults in one kidney transplant study.41 All other studies involved persons older than 16 

years of age. 

Of the RCTs, only one is a head-to-head study of concentration monitoring versus no 

concentration monitoring10 and only two trials (three articles)11,12,29 had the primary aim of 

correlating pharmacokinetic parameters with clinical outcomes. None of the other RCTs were 

designed with this aim in mind and hence they did not provide direct evidence of the utility of 

MPA measurements as they related to clinical outcomes. 

Method of MPA Monitoring. MPA monitoring took the form of full AUC measurements 

over a 12 hour period (AUC0-12 – seven to 10 plasma or serum samples) in 17 reports.11,12,17,26-

30,32,33,35,36,46,52,66,67,106 One study37 used AUCs based on five serum samples. The number of 

samples was not reported in three studies.31,34,43

Single sample limited sampling strategies included predose (i.e., C0, Cmin, or C12) in 59 

studies,7,8,11,12,14-20,22,24-28,30,32,33,36-42,44-50,52-62,64,66-76,106,120 2 hour post dose concentration (C2) in 

two studies,54,57 peak (or maximal or Cmax) in 11 studies,11,17,26,36,43,51,52,54,66,75,76 C30min in two 

studies,33,67 C40min in three studies,21,54,66 and C60min in two studies33,54 Three sample limited 

sampling strategies included AUC based on C0, C0.5, C2

43,63,64,77 AUC based on C20min, C1, C3,10

and AUC based on C0, C75min, C4.

17,26 Four sample limited sampling strategies included AUC 

based on C0, C1, C2, C4

57 and AUC based on C0, C1, C3, C6.

13,59,65 The five sample limited 

sampling strategy included AUC based on C0, C20min, C40min, C75min, C120min.

17-21,26 The seven 

sample limited sampling strategy included AUC based on C0, C1, C2, C3, C4, C6, C9.

76 A final 

strategy was AUC0-9 (sampling times not provided).49

Rejection. Thirty studies, (32 reports) contained evidence showing that a method of MPA 

monitoring is associated with incidence of rejection (Tables 7 to 10).7,8,10-12,17,19,26-33,38-

49,54,57,59,63,64 Conversely, 29 studies, (30 reports) contained evidence against such associations 

(Tables 11 to 14).11,13,15,17,19,24-26,28,34-37,42,45,49-62,65 

In the first published RCT that involved direct, head-to-head comparisons of monitoring 

versus no monitoring, Le Meur et al.10 found that the incidence of treatment failure (composite of 

death, graft loss, acute rejection, and MMF discontinuation) was significantly lower in the 

concentration-controlled group (that used LSS of C20min,C1, and C3 developed by Bayesian 

methods, to target an AUC of 40 mg h/L) compared with the fixed dose group (29.2 percent vs. 

47.7 percent, p=0.03). The percentage of acute rejection (12.3 percent vs. 30.7 percent, p=0.01) 

and biopsy-proven acute rejection (7.7 percent vs. 24.6 percent, p=0.01) were also lower in the 

concentration-controlled group. Cox proportional hazards regression analyses also found that the 

group factor (concentration-controlled vs. fixed dose) was the most powerful indicator of acute 

rejection (hazard rate ratio [HRR]=1.67, p=0.017); after other nonsignificant variables were 

deleted, the group factor was the only significant predictor of acute rejection (HRR=1.65; 95 

percent CI=1.09, 2.54; p=0.02).10

An RCT11,12 in which kidney transplant recipients were assigned to one of three pre-defined 

MPA AUC0-12 showed incidences of biopsy proven acute rejection to be 27.5 percent, 14.9 

percent, and 11.5 percent respectively in each group (p=0.043). Although all three target values 

were exceeded after day 21, there was a significant association between the median natural 

logarithm of MPA AUC0-12 and biopsy proven acute rejection (p<0.001). Based on logistic 

regression analysis, MPA AUC0-12 values of 15 mg·h/L, 25 mg·h/L, and 40 mg·h/L are expected 
34

to yield 50 percent, 75 percent, and 90 percent of maximal achievable efficacy (with a 4 percent 

change in efficacy for every 1 mg·h/L change in AUC at the midpoint of the logistic curve). 

Univariate logistic regression p-values between biopsy proven rejection vs. MPA AUC0-12, MPA 

Cmax, MPA C0, and MMF dose were: < 0.0001, 0.0008, 0.0049, and 0.0918, respectively. The 

authors write that statistical significance is lost when only the first three predose concentrations 

are used in the logistic regression analysis. Consequently, they caution against basing dosage 

adjustments on a limited number of predose concentrations.12

Another study (two reports)7,8 reported rejection outcomes for patients on fixed dose MMF 

(phase I) versus patients whose MMF dose was adjusted to meet target MPA predose 

concentrations of 2.5 to 4.5 mg/L (phase II). In the phase I group, the mean MPA predose 

concentrations were 3.6 mg/L with no episodes of rejection, 2.2 mg/L with one or two rejection 

episodes, and 1.5 mg/L with three rejection episodes (p-value not provided). In the phase II 

group, three patients (all of whom experienced only one rejection episode each) had MPA 

predose concentrations of 0.7 mg/L, 1.3 mg/L, or 0.9 mg/L. The authors also suggested that 

mean MPA plasma predose concentrations greater than 3.0 mg/L were not associated with 

rejection, although no details were provided in the reports. 

In an RCT of kidney transplant recipients, Hazzan et al.28 found that an MPA AUC0-12 cut off 

of 50 mg·h/L was associated with risk for acute rejection in a multivariable Cox regression 

analysis (adjusted hazard ratio: 0.79; 95 percent CI: 0.64 to 0.98). The authors suggested that 

this cut off “needs to be confirmed by further investigations”. In the same study, an MPA 

predose concentration cut off of 0.5 mg/L was not associated with risk for acute rejection in the 

multivariable model, but it was associated in a simple Cox model (unadjusted hazard ratio: 0.53; 

95 percent CI: 0.30 to 0.94). 

In nine case series, ROC curves were generated to determine whether a particular PK 

parameter could differentiate patients with acute rejection from patients without acute rejection. 

Weber et al.26 found that C0, C12, AUC0-12, and AUC (based on C0, C75min, C4) were able to 

differentiate between pediatric kidney transplant recipients with and without acute rejection. An 

AUC0-12 of 33.8 mg.h/L (measured using HPLC assay) had a diagnostic sensitivity of 80 percent 

and a diagnostic specificity of 57 percent; AUC0-12 (measured using EMIT assay) was 36.1 

mg.h/L. A C12 (HPLC) of 1.2 mg/L had a diagnostic sensitivity of 80 percent and a diagnostic 

specificity of 60 percent; C12 (EMIT) was 1.4 mg/L. In contrast, Cmax and AUC (based on C0, 

C0.5, C2) did not perform as well (p=0.24 and p=0.06 respectively) in differentiating between 

rejectors and non-rejectors.26 Weber et al.,17 in a second case series of pediatric kidney 

transplant recipients, found MPA C12, AUC0-12, AUC (based on C0, C75min, C4), and AUC (based 

on C0, C0.5, C2) were able to differentiate between patients with and without acute rejection. An 

AUC0-12 (HPLC) of 33.8 mg·h/L had a diagnostic sensitivity of 75 percent and a diagnostic 

specificity of 64.3 percent. A C12 (HPLC) of 1.2 mg/L had a diagnostic sensitivity of 83.3 

percent and a diagnostic specificity of 64.3 percent. Conversely, C0 and Cmax did not perform as 

well (p=0.07 and p=0.10 respectively) in differentiating between rejectors and non rejectors. In 

their third case series of pediatric kidney transplant recipients, Weber et al.63 again found that 

AUC (based on C0, C0.5, C2) was able to differentiate between patients with and without 

rejection. An AUC cut off of 36.8 mg·h/L had a prognostic sensitivity of 66.7 percent and a 

prognostic specificity of 61.9 percent.63

Results from the other six case series are as follows: Armstrong et al.27 showed that an MPA 

AUC0-12 cut off of 29.5 mg·h/L (HPLC) for acute rejection in pediatric kidney transplant 

recipients had a diagnostic sensitivity of 66.7 percent and a diagnostic specificity of 79.4 
35

percent; MPA AUC0-12 cut off was 36.1 mg·h/L (EMIT). An MPA C0 cut off of 1.0 mg/L 

(HPLC) for acute rejection had a diagnostic sensitivity of 77.8 percent and specificity of 64.5 

percent; MPA C0 (EMIT) was 1.3 mg/L.27 The ROC curve analysis performed by Lu et al.48 in 

kidney transplant recipients showed significant correlations between MPA C0 and clinicial 

events (toxity and rejection), and revealed a diagnostic sensitivity (65.1 to 84.6 percent) and 

specificity (74.7 to 84.7 percent). Pawinski et al.64 found that an AUC (based on C0, C0.5, C2) cut 

off of 27.5 mg·h/L for acute rejection in kidney transplant recipients had a diagnostic sensitivity 

of 81.2 percent and a diagnostic specificity of 93.4 percent. The C0 cut off for acute rejection of 

1.1 mg/L had a diagnostic sensitivity of 63.4 percent and a diagnostic specificity of 85.3 percent. 

In a similar case series, Pawinski et al.43 found that an AUC (based on C0, C0.5, C2) cut off of 

24.1 mg·h/L for acute rejection had a diagnostic sensitivity of 77.8 percent and diagnostic 

specificity of 91.7 percent. A C0 cut off of 0.8 mg/L had a diagnostic sensitivity of 59.3 percent 

and diagnostic specificity of 83.3 percent. A Cmax cut off of 5.1 mg/L had a diagnostic 

sensitivity of 66.7 percent and diagnostic specificity of 87.5 percent. Borrows et al.14 found that 

a median MPA C0 of 1.60 mg/L best differentiated between kidney transplant recipients with and 

without acute rejection in the first 30 days post transplant. However, no association was 

observed between MPA concentration and five specific acute rejection episodes that occurred 

after 30 days. Kiberd et al.57 found that the best cut off point for predicting rejection in kidney 

transplant recipients was an AUC (based on C0, C1, C2, C4) of 22 mg.h/L (sensitivity 82 percent, 

specificity 64 percent, negative predictive value 89 percent, positive predictive value 30 percent). 

Graft function or other efficacy parameter. Two studies18,106 looked at methods of MPA 

monitoring and the incidence of graft function (Tables 15 and 16). The first study18 was a case 

series involving 46 stable kidney transplant recipients. Graft function was defined by creatinine 

clearance (severe graft dysfunction: creatinine clearance less than 20 mL/min). Patients with an 

MPA AUC0-12 cut off greater than 40 μg/mL·h had better graft function than patients with an 

MPA AUC0-12 of 40 μg/mL·h or less. Mean creatinine clearance values were 85.7 mL/min in the 

‘greater than’ group and 64.5 mL/min in the ‘less than’ group (p<0.01). The authors claimed to 

have similar findings for an MPA predose concentration (AUC0-2) cut off of 1.5 μg/mL, but no 

data were reported. MPA AUC0-12 was significantly and positively correlated with creatinine 

clearance (r=0.52, p< 0.01), as was predose concentration (MPA AUC0-2) (r=0.50, p< 0.01). 

A case control study106 of 27 stable kidney transplant patients looked at the correlation of 

MPA AUC0-12, Cmin, and Cmax with IMPDH (Inosine 5'-Monophosphate Dehydrogenase) 

activity, a direct pharmacodynamic parameter of MPA. Although the authors reported that “for 

the majority of the patients an inverse relationship between MPA concentrations and IMPDH 

activity was observed”, patients with comparable MPA AUC0-12, Cmin, and Cmax values exhibited 

different degrees of IMPDH inhibition, which suggests wide interindividual pharmacodynamic 

activity. Furthermore, in MPA-treated patients, baseline IMPDH differences may lead to 

differences in outcome. 

Adverse events. Four studies showed that full AUC (AUC0-12) is associated with adverse 

events. One of these studies was a non randomized controlled trial31 and the three others were 

case series.33,36,46 There were 18 positive studies involving predose concentrations (predose, C0, 

Cmin, or C12): one was an RCT,68 three were prospective cohort studies,39-41 and 14 were case 

series.14,16,33,36,45,48,56,61,69-74 Five studies found other limited sampling strategies to be related to 

adverse events: one was an RCT evaluating C0, C1, C3, and C6

65 and four were case series (one of 

C40min,

66 one of C0, C1, C3, and C6,59 one of both C30min and C60min,59 and one of C30min

67). No 

studies found C2 to be a significant predictor of adverse events (Tables 17-20). 
36

Eleven studies showed that full AUC (AUC0-12) is not associated with adverse events. Two of 

these studies (three reports) were randomized controlled trials,11,12,29 two were prospective cohort 

studies,35,52 and seven were case series.17,26,32,36,37,66,67 There were 24 negative studies of predose 

(C0, Cmin, or C12): three (four reports) were RCTs,11,12,25,75 one was a non randomized controlled 

trial,49 two were prospective cohort studies,20,52 one was a case control study,54 two were 

retrospective cohort studies,22,42 and 15 were case series (Tables 21 to 

24).14,15,17,18,26,36,37,47,57,62,64,66,67,72,76

Two studies (a case control54 and a case series57) found C2 not to be a significant predictor of 

adverse events. Of 16 studies finding other limited sampling strategies to be unrelated to adverse 

events, one was a RCT directly comparing fixed dose versus targeted AUC values based on a 

limited sampling strategy (LSS) of C20min, C1, C3

10, two were RCTs evaluating Cmax,11,75 one was 

a non randomized controlled trial of AUC0-9

49, 3 were prospective cohort studies (one of C0, 

C20min, C40min, C75min, and C120min,

20 one of C0, C1, C3, and C613, and one of Cmax52), one was a case 

control study of 3 different LSSs (i.e., C40min, C60min, and Cmax),54 and 8 were case series (one 

evaluating both C0, C1, C2, C4, C6, and C9 as well as Cmax,

76 one of C0, C0.5, and C2,64 two of Cmax 

,

36,66 one of C0, C1, C2, and C4 ,

57 two evaluating 3 different LSSs of Cmax, AUC0-4 or C0, C75min, 

and C4, and AUC0-2 or C0, C20min, C40min, C75min, and C120min,

17,26 and another evaluating C0, 

C20min, C40min, C75min, and C120min

21). 

A secondary objective of the Le Meur et al. RCT10 was to compare the incidence of adverse 

events in the concentration-controlled versus the fixed dose groups. Overall, 97 percent and 90 

percent of patients in the concentration-controlled and fixed dose groups, respectively, reported 

one (or more) adverse events. There was no significant difference (p>0.05) in incidence of total 

adverse events and specific gastrointestinal events, anemia, leucopenia, or infections between the 

two groups, except for herpes infections which occurred more frequently in the concentrationcontrolled group (8 vs. 1 event, p<0.05).10

The van Gelder et al.12 and Hale et al.11 RCT in kidney transplant patients compared adverse 

events for subjects with planned dose adjustments based on different target MPA plasma 

concentrations.11,12 They found that premature study withdrawal due to adverse events was not 

associated with the median natural logarithm of MPA AUC0-12 (p=0.434) nor the median natural 

logarithm of C0 (p=0.512). Associations between each specified adverse effect (i.e., diarrhea, 

nausea, leucopenia, CMV, urinary tract infection, and abdominal pain) and MPA AUC0-12, MPA 

Cmax, and MPA C0 were all not statistically significant (p>0.05).11 One explanation for the lack 

of statistically significant associations is that the data anlysis in the trial was undertaken before 

the ascertainment of total MPA concentrations over time post transplant. Median AUC was used 

instead, and patients with higher median AUCs tended to remain in the study longer than patients 

with adverse events.6

A case series conducted by Hubner et al.56 in kidney transplant recipients reported adverse 

events for subjects with planned dose adjustments based on MPA predose concentrations. The 

data showed that MPA predose concentrations for patients with adverse events were higher 

relative to patients without adverse events (2.13 versus 1.53 mg/L; p< 0.001). Shaw et al.20

evaluated two groups of kidney transplant recipients (i.e., MPA AUC-controlled versus MPA C0-

controlled dose adjustment) and stated that the occurrence of diarrhea was not associated with 

high concentrations of MPA AUC, predose, or MPAG predose values. However, they did not 

provide quantiative data for their claim.20

In three case series,14,33,48 the authors generated ROC curves to determine whether a 

particular PK parameter could differentiate between patients with and without adverse events. 
37

Mourad et al.33 found that an MPA C0 cut off of 3 mg/L for toxicity in kidney transplant 

recipients had a diagnostic sensitivity of 38.7 percent and a diagnostic specificity of 91.5 percent. 

An MPA C60min cut off of 8.09 mg/L for toxicity had a diagnostic sensitivity of 77.8 percent and 

a diagnostic specificity of 67.4 percent. Lastly, an MPA AUC0-12 cut off of 37.6 mg·h/L for 

toxicity had a diagnostic sensitivity of 83.3 percent and a diagnostic specificity of 59.6 percent. 

The ROC curves were not statistically significantly different between these parameters.33 

Borrows et al.14 found the median C0s that best discrimated between patients with and without 

the following adverse events: leucopenia (2.60 mg/L), anemia (2.75 mg/L), diarrhea (2.40 mg/L), 

and viral infection (3.20 mg/L). The Lu et al.48 ROC analysis showed significant correlations 

between MPA C0 and clinicial effects (rejection and toxicity) in kidney transplant recipients,with 

a dignostic sensitivity of 65.1 to 84.6 percent and specificity of 74.7 to 84.7 percent. 

Question 4. Does the Evidence for Monitoring MPA Differ by any of 

the Following? 

Forty eight studies were included to address the six components of the key question. Study 

characteristics are shown in Evidence Table 1, Appendix C∗. 

4a: Age 

Six studies17,18,23,69,112,122 addressed the effect of age on MPA PK parameters in kidney 

transplant patients. Three of these studies included adult patients only,18,69,122 two included 

pediatric patients only,17,23 and one compared pediatric with adult kidney transplant patients.112 

One other study involved pediatric heart transplant patients.55 The findings of these studies 

(Table 25) are summarized below. 

One of the adult only studies (n=117) of kidney transplant patients did not find an association 

between age and MPA predose concentrations.69 The other adult study (n=46) found that 

patients in the MPA AUC0-12 >40 μg/mL·h group were slightly but significantly younger than 

patients in the <40 μg/mL·h group.18

Wang et al. compared the pharmacokinetic characteristics of MPA among elderly (defined as 

over 60 years of age) Chinese renal transplant recipients (n=24) to younger adults (n=24). 122

This study found that the MPA AUC was significantly lower in the elderly compared to the 

younger adult group receiving the same dose of MMF, although the differences in predose, peak 

concentrations, or peak times were not significant.122

Turning to the pediatric only studies, the Bunchman et al.23 multicenter, open label, single 

arm study of MMF oral suspension (n=100) showed no clinically significant differences in MPA 

and MPAG PK parameters among different age groups. No associations were observed between 

low MPA and MPAG plasma concentrations and the incidence of acute rejection. Similarly, no 

associations were found between adverse events and PK parameters. Conversely, an open label, 

longitudinal evaluation of the PK-pharmacodynamic relationship for total and free MPA in 

pediatric kidney transplantation (n=54) by Weber et al.,17 showed that in the first week post 

transplant, but not at later, PK sampling periods, low MPA AUC0-12 values were associated with 

young age. The same study showed that both MPA AUC0-12 and predose MPA concentrations 

were significantly associated with the risk of acute rejection in this patient population. By ROC 

 

∗ Appendixes and Evidence Tables for this report are provided electronically at http://www.ahrq.gov/clinic/tp/mpaorgtp.htm
38

analysis, an AUC0-12 of 33.8 mg·h/L in the initial phase post transplant had a diagnostic 

sensitivity of 75 percent and a diagnostic specificity of 64 percent for discrimination of patients 

with acute rejections. The respective discrimination threshold for the MPA predose 

concentrations was 1.2 mg/L, with a sensitivity of 83 percent and a specificity of 64 percent. 

In the Weber et al.112 pediatric (n=18) versus adult (n=10) kidney transplant study, which 

was an open label, prospective study to evaluate MPA PK parameters, children displayed 

concentration-time profiles of total and free MPA after oral administration of 600 mg/m2

 body 

surface area twice daily that, in general, were comparable to the profiles of adults receiving 

1,000 mg MMF twice daily. This was in the first three weeks post transplant. Mean MPA 

AUC0-12 in pediatric patients one week post transplant was 40 percent higher than in adults, but 

comparable at three weeks. The AUC0-12 values of free MPA at one and three weeks did not 

differ between children and adults. The authors found higher AUC0-12 values for the MPA 

metabolite MPAG in adult patients compared with children, but this was most likely due to the 

higher incidence of primary transplant dysfunction in the adults.112

The Dipchand et al.55 retrospective study involving pediatric heart transplant recipients 

(n=44) found that increased MPA predose concentrations were significantly associated with 

older children, thereby implying that higher MMF doses may be required to achieve appropriate 

MPA concentrations in very young patients. 

4b: Gender 

The literature search failed to yield studies of direct relevance to this question. Ideally, 

studies to answer this question would examine the relationship between MPA PK parameters and 

patient outcomes (e.g. rejection, adverse events) for men versus women. However, three 

studies29,52,69 in kidney transplant patients did examine associations between gender and MPA 

PK parameters (Table 26). Of these studies, two29,69 reported a difference in MPA PK 

parameters between men and women, while the third52 reported no difference. None of the 

studies examined how the associations might affect patient outcomes. 

 The Lu et al.29 open label, randomized evaluation of MPA PK parameters in Chinese 

primary kidney transplant patients (n=29) showed a statistically significant difference in MPA 

AUC0-12 according to gender. MPA AUC for females was higher than that of males by 34.3 

percent even though females were receiving the same doses of MMF (p=0.0006). In this study, 

MPA AUC0-12 was lower in the patients who experienced an acute rejection compared to patients 

who did not (40.93 + 14.28 μg·h/ml versus 53.88 + 12.70 μg·h/ml; p=0.038). However, MPA 

AUC0-12 values were not stratified by gender. Similarly, in the Borrows et al.69 prospective study 

of kidney transplant recipients (n=117), multivariable analysis showed that female gender was 

associated with higher predose concentrations compared to males (effect size: 1.22; 95 percent 

CI: 1.12 to 1.31; p=0.002). In contrast, a prospective study, by Kuypers et al.,52 of 100 de novo, 

deceased donor, renal transplant patients showed that MPA PK parameters were not influenced 

by recipient gender. The same study found no significant relationship between acute rejection 

and MPA AUC0-12, C0, or Cmax. 
39

4c: Ethnicity 

Two studies20,69 retrieved in the literature search contained data linking ethnicity and MPA 

PK parameters (Table 27). Both studies involved kidney transplant patients and suggested there 

is no association between ethnicity and MPA PK parameters. 

The Shaw et al. study20 found no significant differences in MPA AUC values over the three 

month study period in African Americans (n=13) compared to Caucasians (n=20). The MPA 

predose concentrations were also not statistically significantly different between groups, 

although the values were generally higher in African Americans. The incidence of acute 

rejection at three months was 30.8 percent in the African Americans and 15 percent in the 

Caucasians (p=0.288). The authors suggest that the difference in acute rejection rates may have 

been due to differences in immune response. Regarding adverse events, the occurrence of 

diarrhea was not associated with high concentrations of either total or free MPA AUC, predose, 

or MPAG predose values. The Borrows et al. study69 (n=117) showed no association between 

ethnicity (White, Indo-Asian, Afro-Caribbean, other) and MPA predose concentrations. 

4d: Concomitant use of Calcineurin Inhibitors (e.g., Tacrolimus, 

Cyclosporine) 

Studies of direct relevance to this question compared one calcineurin inhibitor (CNI) to 

another in terms of patient outcomes (e.g., acute rejection or adverse events) related to MPA 

monitoring. Other studies addressed the effects of CNIs on MPA PK parameters. In our search, 

we found 12 such studies involving renal transplant patients,13,29,33,36,38,49,63,64,69,76,77,108 three 

involving cardiac transplant patients,45,58,70 and two involving liver transplant patients.40,107 An 

additional study compared liver and small bowel transplant recipients to renal transplant 

recipients (Table 28).24

Most studies found that the type of concomitant CNI used for maintenance 

immunosuppression influenced MPA PK parameters. Seven studies of renal transplant recipients 

(n=29 to 290)13,29,33,38,64,76,77 and two studies of cardiac transplant recipients (n=20 to 26)45,58

showed that patients receiving concomitant tacrolimus had significantly higher MPA predose 

concentrations compared to patients receiving concomitant cyclosporine. For example, in 

Atcheson et al.’s prospective study13 of 42 de novo renal transplant patients, patients in the 

cyclosporine treated group had a mean total MPA predose concentration (for the same dose of 

MMF) that was approximately half of what patients had in the tacrolimus treated group. Most of 

these studies also found that not only the predose, but the MPA AUC as well, was significantly 

higher with co-administration of tacrolimus compared to cyclosporine.29,33,64,76,77 In the recent 

Heller et al. study77 performed as a sub-study of a phase IV open, prospective, randomized 

controlled trial comparing fixed dose versus concentration-controlled MMF regimens for renal 

transplant recipients, though MPA AUC was higher in patients on concomitant tacrolimus 

compared with cyclosporine, the plasma AcMPAG and MPAG concentrations were substantially 

lower in the former group. These data support the assumption that cyclosporine inhibits the 

biliary excretion of MPAG and AcMPAG, therefore potentially reducing the risk of intestinal 

injury through enterohepatic recycling of MPA and its metabolites. In this study significantly 

more patients on tacrolimus suffered from diarrhea compared to cyclosporine (31.1 percent 

versus 12.7 percent, respectively). 
40

One study, by Naito et al.,108 involving 25 Japanese renal transplant recipients showed no 

significant difference in MPA predose concentrations between tacrolimus versus cyclosporine 

treated groups. There was also no difference in CNI treated patients compared with patients not 

receiving concomitant CNIs. The Tredger et al. study40 evaluating 95 adult liver transplant 

patients found median MPA concentrations were lower with tacrolimus than with either 

cyclosporine or no CNI comedication.40 Ringe et al.107 found that a two hour dosing interval 

between MMF and Tacrolimus reduced MPA related diarrhea, resulting in higher Tacrolimus 

levels.107

4e: Concomitant use of Other Medications 

Five studies with relevance to this question were retrieved in the literature search (Table 

29).22,50,65,69,78 The Mudge et al.65 open label, RCT in renal transplant recipients (n=40) found no 

significant effect of oral iron supplements on MMF absorption as measured by MPA AUC 

measurements. Patients who experienced toxicity showed significantly higher MPA AUC 

measurements than those who tolerated MMF well. However, there were no significant 

differences in the occurrence of MMF toxicity between the three groups of no iron versus iron 

with morning MMF dose versus iron spaced four hours apart from morning MMF dose. There 

were also no differences between the three groups in the observed frequencies of anemia, 

leucopenia, thrombocytopenia, infection or gastrointestinal intolerance. Rejection rates were 

similar between the study groups. 

A randomized, open label, crossover study, by Wolfe et al.,78 involving 12 male kidney 

transplant recipients evaluated the PK parameters of MPA in patients given 1,500 mg oral MMF 

alone, MMF and 5 mg/kg intravenous ganciclovir, and ganciclovir alone in separate phases with 

at least a one week washout period in between. The single dose PK parameters of MPA and its 

glucuronide metabolite, MPAG, were unchanged by the addition of ganciclovir. Neither the 

renal elimination nor the metabolism of MPA to MPAG was altered with the addition of 

ganciclovir, as indicated by the percentage of dose excreted as MPAG and the MPAG:MPA 

AUC ratio. 

The Borrows et al. study69 involving 117 renal transplant patients found that treatment with 

oral augmentin, ciprofloxacin, or metronidazole was associated with a reduction in MPA predose 

concentrations, but no effect was seen with the use of intravenous antibiotics (vancomycin, 

tazocin, and carbopenems). The authors explain the lower MPA predose concentration in 

patients treated with oral antibiotics as being due to a reduction of enterohepatic circulation. An 

antibiotic induced reduction in enteric organisms possessing glucuronidase leads to decreased 

recycling of MPAG back to MPA within the bowel and to a consequent reduction in the 

secondary peak of MPA absorption. The same study found no association between MPA 

predose concentrations and the use of oral prednisolone, ferrous sulfate, calcium carbonate, or 

ganciclovir. 

Merkel et al.’s22 retrospective study of 35 kidney transplant recipients showed no effect of 

concomitant steroids or furosemide on MPA or MPAG predose concentrations. The same study 

showed a positive correlation between xipamide (a thiazide diuretic) and MPA predose and a 

negative correlation between diltiazem and MPA predose. 

Kreis et al.’s50 randomized trial of kidney transplant patients (n=78) receiving sirolimus or 

cyclosporine showed that the average daily doses of MMF were significantly lower in the 
41

sirolimus group, while MPA predose concentrations were significantly higher in the sirolimus 

group. 

4f: Comorbidity 

Studies addressing the effect of renal function on MPA PK parameters provided mixed 

findings (Table 30). In one study of 46 kidney transplant patients, plasma MPA predose 

concentrations and MPA AUC0-12 were positively and significantly correlated with patients’ 

creatinine clearance values.18 A Japanese study involving 25 kidney transplant patients found 

that MPA and MPAG predose concentrations were influenced by renal function in cyclosporine 

treated recipients, but not in patients treated with tacrolimus.108

In a study comparing eight kidney transplant patients with renal insufficiency (defined as 

creatinine clearance < 20 ml/min) and 15 renal transplant patients with preserved renal function, 

Kaplan et al.21 found that the average free fraction of MPA and the free MPA AUC was 

approximately double in patients with chronic renal insufficiency compared to patients with 

normal renal function. MPAG average concentrations in patients with renal insufficiency were 

significantly higher than patients with preserved renal function. Half of the patients with chronic 

renal insufficiency developed leucopenia within one month of the kinetic study. This adverse 

effect occurred in patients with the highest free MPA AUC. None of the patients with preserved 

renal function developed this complication.21 In another study, Shaw et al.20 found that impaired 

renal function lowered the MPA AUC in both African Americans and Caucasians in the early 

post transplant period. This was attributed to an increased free fraction of MPA in the patients 

with graft dysfunction as a result of reduced binding of MPA to serum albumin. An open label 

prospective study evaluating the MPA PK parameters in pediatric kidney transplant patients 

(n=18) compared with adults (n=10) reported a tight inverse correlation between plasma MPAG 

AUC0-12 values and GFR both in children (r=-0.70, p<0.001) and adults (r=-0.83, p<0.001).112

In another study (n=31), Johnson et al.123 stratified subjects based on their iohexol clearance 

and found that MPA clearance was not associated with changes in GFR. Cmax tended to increase 

as GFR decreased. MPAG clearance correlated well with GFR (r2=0.90). Clearance of MPA 

and MPAG were unaffected by hemodialysis, with losses during hemodialysis representing less 

than 10 percent of the dose administered. Morgera et al.116 studied the impact of peritoneal 

dialysis on MPA PK parameters in five patients following renal transplantation. MPA and 

MPAG AUC decreased during peritoneal dialysis. 

In a randomized, placebo controlled trial (n=57 renal transplant patients), the concentrations 

for MPA were not affected by graft function or dialysis; however, there was an increase of 

MPAG with decreasing graft function.25 In a study of eight kidney transplant patients, renal 

dysfunction was associated with altered PK parameters of MPA, particularly increased AUC0-12 

of MPAG, MPA free fraction, and AUC0-12 of free MPA. The perturbed PK parameters 

normalized with improving renal function.113 Another prospective study evaluated the impact of 

peritoneal dialysis on the PK parameters of MPA in five kidney transplant recipients. They 

found a significant inverse correlation between GFR and MPA-AUC and between GFR and 

MPAG-AUC.115

The effect of liver function on MPA PK parameters is not entirely clear. In the Zakliczynsk 

et al.70 study of 76 cardiac transplant patients, a significant positive correlation was observed 

between MPA concentrations and cyclosporine in patients with impaired liver function. 

However, no correlation was noted between MPA predose and cyclosporine in patients without 
42

liver dysfunction. Brunet et al.66 found no significant correlation when the effect of liver 

function tests on MPA concentration and AUC was examined in 15 primary cadaveric liver 

transplant recipients. 

In another study, by Naesens et al.,79 involving 95 kidney transplant recipients, investigators 

evaluated the association between single nucleotide polymorphisms (SNP) in the MRP2 gene 

and MPA PK parameters. In patients not carrying the MRP2 C-24T SNP gene, the investigators 

found a marked difference in MPA exposure between patients with and without liver 

dysfunction. Patients with mild liver disease had significantly lower MPA dose corrected 

predose concentrations, a lower dose corrected MPA AUC0-12, and higher calculated MPA 

clearance. 

Question 4. Summary 

Based on the current evidence available, some of the six components of this question appear 

to influence MPA PK parameters. However, none of the included studies investigated whether 

PK parameter levels, stratified by each component, were associated with outcomes such as 

rejection or adverse events. Regarding age, the evidence was equivocal. In pediatric 

populations, younger children were found to require a higher MMF dose to achieve a specified 

MPA concentration. Regarding gender, the evidence appears to indicate that PK parameters are 

higher for females versus males. Race and ethnicity do not appear to influence MPA PK 

parameters. Calcineurin inhibitors are co-administered frequently with MMF and the bulk of the 

evidence found that exposure to MPA is higher in patients receiving tacrolimus compared to 

cyclosporine, with lower doses of MMF required in combination with tacrolimus to achieve 

adequate MPA exposure. Total MPA PK parameters were generally higher in persons with renal 

insufficiency, although one study found lowered MPA AUC in the early post transplant period. 

Question 5. What is the Short- and Long-Term Cost-Effectiveness of 

Avoiding Acute Rejection due to MPA Monitoring? 

Findings from the abstracted studies. None of the abstracted studies contained any data on 

the cost-effectiveness associated with MPA monitoring. There is no evidence in the literature on 

the cost-effectiveness of MPA monitoring. 

Quality Assessment of Abstracted Studies 

Twelve of the 89 abstracted studies were RCTs10-12,25,28,29,34,50,51,65,68,78 and the remainder 

were observational studies (primarily case series). The quality of the RCTs was fair to good. 

Eleven studies contained baseline comparisons of treatment groups (three had minor differences 

on one or two variables), 11 used ITT analyses, eight clearly reported the methods used to 

measure MPA, and 10 had clear definitions of outcomes related to measuring MPA. Conversely, 

reporting of some essential features of trial design was lacking. The method of randomization 

was described in five studies and the means of treatment allocation was described in two studies. 

The authors of three studies reported that subjects and persons assigned to measure MPA were 

blinded; four studies contained reports of blinding amongst outcome assessors. One of the 

RCTs10 contained reports of differential losses to followup. Although it appears from the 
43

published reports that there were no losses to followup in the other reports, the authors did not 

specifically state whether any such losses occurred. 

Compared to the RCTs, the 77 observational studies suffered from numerous reporting 

problems. Virtually all of the studies lacked reports of blinding among subjects (n=73), persons 

measuring MPA (n=74), and outcomes assessors (n=75). Differential losses to followup were 

not reported in 61 studies. The authors of only 29 studies made an attempt to control for 

confounding. Some aspects of reporting were good, though, as the authors of most of the 

observational studies described the methods used to measure MPA (n=68) and clearly defined 

their outcomes (n=69). 

The most troublesome aspects of study quality were the failure to report blinding in a 

majority of the studies and the failure to control for confounding in most of the observational 

studies. For blinding, it is often debatable whether the issue reflects poor study quality or poor 

reporting. For confounding, the very nature of observational studies suggests that the influence 

of ‘third party’ variables should be considered in the design or analysis stage. To do otherwise is 

a serious omission.
44

Table 1. Studies showing that rejection is related to MMF dosage 

Study Population Treatment Major Findings/ 

Satoh35 2005 

Study design: Prospective Cohort Length of followup: 28 days 

Organ transplanted: Kidney (Renal) Age: Mean AZA: 37.9 +/- 11.5y MMF: 44.3 +/- 11.6y 

Dose: 1.0 – 2.0 g/day Concomitant medications: Tacrolimus Methylprednisolone Prednisone 

MMF dose per bodyweight was than those without AR (25.1 vs. there was no significant differen

patients with AR compared to th59.5 μg·h/L, p=0.081) 

Satoh30 2006 

Study design: Case series Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 41.2 +/- 2.1y Range 21 – 66y 

Dose: 2 g/day Concomitant medications: Tacrolimus Methylprednisolone Corticosteroids 

Single dose/bodyweight in patiewere 12.46 and 16.99 mg/kg, re

Takahashi31 1995 

Study design: Non randomized controlled trial Length of followup: 12 weeks 

Organ: Kidney Age: Inclusion requirement ≥16y 1000 mg/d: Mean 37.7 

± 6.3 y 

2000 mg/d: Mean 38.5 

± 12.2 y 

3000 mg/d: Mean 41.0 

± 10.3 y 

Dose: 1000, 2000, or 3000 mg/day Concomitant medications: Cyclosporine Steroids (no description) 

The following percentages of parejection episodes in the 1000 mmg MMF dose groups: 25.0%, 5respectively (p values not given

Abbreviations: AR=Acute rejection, AUC=Area-under-the-concentration-time curve, AZA=Azathioprine, MMF=Mycophenolate Mofetil, MPA=Mycoreported, y=Years 
45

Table 2. Studies showing that rejection is not related to MMF dosage 

Study Population Treatment Major Findings/ Comments 

Barbari53 2005 

Study design: Case control Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 39y Range 20 – 67y 

Dose: 1 g BID range 1 - 2.5 g/day Concomitant medications: Cyclosporine Prednisone 

There was a poor association between clinical events (primalymphocyte counts [an indicator of immune responsiveness]MPA predose concentrations (r=0.0803). 

Hale11

1998 Study design: RCT Length of followup: 20 weeks 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement > 18 y Range: L: 47.8 +/- 11.5 y, I: 46.9 +/- 13.8y, H: 50.6 +/- 10.5y 

Dose: L: 0.45 g BID then adj I: 0.95 g BID then adjusted H: 1.7 g BID then adjusted Concomitant medications: Cyclosporine Corticosteroids 

Univariate logistic regression p values between biopsy-proveAUC0-12, MPA Cmax, MPA C0, and MMF dose were: < 0.0001

0.0918, respectively (i.e., not significant for MMF dose). In bregression analysis, MPA AUC remains statistically significa

C0, and MMF dose are all not significant. 

Hazzan28 2005 

Study design: RCT Length of followup: 1 year 

Organ transplanted: Kidney (Renal) Age: Mean CsA 42.5 +/- 12.1y MMF 45.1 +/- 11.2y 

Dose: CsA group MMF dose = 1.93 +/- 0.2 g/day then withdrawn to 0, MMF group MMF dose = 1.99 +/- 0.1 g/day Concomitant medications: Cyclosporine 

No significant difference was observed in MMF dose betweethose without (2.0 vs. 1.9 g/day). 

Kuypers36 2004 

Study design: Case series Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Median 51.5y 

Dose: 0.5 g BID or 1 g BID Concomitant medications: Tacrolimus Methylprednisolone Daclizumab 

Same study subjects as Kuypers52

MMF dose was not significantly different in patients with acuwith those without (17.6 mg·kg-1·day-1 vs. 20.9 mg·kg·day, 

Abbreviations: ADJ=Adjusted, AR=Acute rejection, AUC=Area-under-the-concentration-time curve, BID=Twice Daily, C0=Predose Trough Serum or 

Cmax=Maximum Serum or Plasma Concentration, CsA=Cyclosporin A, H=High, I=Intermediate, L=Low, MMF= Mycophenolate Mofetil , MPA=Myco

Reported, RCT=Randomized Controlled Trial, y=Years
46

Table 2. Studies showing that rejection is not related to MMF dosage (continued)

Study Population Treatment Major 

Kuypers52 2003 

Study design: Prospective Cohort Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Median 51.5y 

Dose: 1 g/day or 2 g/day Concomitant medications: Cyclosporine Tacrolimus Methylpredisolone 31 patients received daclizumab 

Same study 

The percentbiopsy-provdiffer betwegroups. Onesurvival also different betgroups. 

Mourad33 2001 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Range 32-68y Median 49y 

Dose: 500 mg BID + adjustment for side effects Concomitant medications: Tacrolimus Corticosteroids 

MPA measuacute rejecta fixed dose were: MPA mg/L; MPA 

104.9 mg.h/

Yamani42 2000 

Study design: Retrospective Cohort Length of followup: 179 +/- 52 days 

Organ transplanted: Heart (Cardiac) Age: Mean 36 +/- 14y 

Dose: 2 g/day Concomitant medications: Cyclosporine Tacrolimus Prednisone 

There was nmean MMF predose consamples witany time po
47

Table 3. Studies showing that adverse events are related to MMF dosage 

Study Population Treatment Major Findings/ Comm

Bilbao62 2006 Study design: Case series Length of followup: mean 39 ± 20 

months; range 3 to 72 months 

Organ transplanted: Liver Age: Mean 59 ± 6y 

Dose: Initial dose of 500 mg/12h; reaching dose of 1 g each 12h for 2 weeks. Concomitant medications: Cyclosporine (Neoral) Tacrolimus 

Dose adjustments were based on tolerability not on predose concentrations although they concentrations over 4 μg/mL”. 

Borrows14 2006 

Study design: Case series Length of followup: minimum of 12 months; median 25 months; range 13-38 months 

Organ transplanted: Kidney (Renal) Age: Mean 46 +/- 9y Range 37 – 55y 

Dose: 750mg – 2g/day Concomitant medications: Tacrolimus Methylprednisolone Prednisone Corticosteroids Ganciclovir (for 3 months) Co-Trimoxazole (for 6 months) Isoniazid and Puridoxine (used in indoasians and those with previous TB) Basiliximab or Daclizumab (79 patients) 

In multivariate analysis, total daily MMF dose associated with anemia and MMF-associate0.003, respectively), but not with leucopeniarejection. 

Borrows69 2005 

Study design: Case series Length of followup: 30 months; median 19 months; range 6 – 30 months 

Organ transplanted: Kidney (Renal) Age: Mean 46 +/- 9y Range 37-55y 

Dose: 250-1500 mg/day corrected for 

body weight Concomitant medications: Tacrolimus Methylprednisolone Prednisone 

A higher MMF dose had been given to patiediarrhea (1750 mg vs. 1371 mg, p=0.007). 

Abbreviations: BID=Twice Daily, CsA=Cyclosporin A, GI=Gastrointestinal, H=High, I=Intermediate, L=Low, MMF=Mycophenolate Mofetil, RCT=Ry=Years
48

Table 3. Studies showing that adverse events are related to MMF dosage (continued) 

Study Population Treatment Major Findings/ Com

Deierhoi75 1993 

Study design: RCT Length of followup: phase I trial: mean 26 months; range 22 - 28 months; rescue: mean 20 months; range 16 - 24 months 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement phase I: older than 18y, Rescue: older than 16y 

Dose: Phase I: 1500 - 3000 mg/day Rescue: 2000 mg/day and 3000-3500 mg/day if no response in first week Concomitant medications: Phase I: Minnesota antilymphocyte globulin(MALG) Methylprednisolone Cyclosporine Corticosteroids Rescue: Predisone Cyclosporine Minnesota antilymphocyte globulin(MALG) Azathioprine 

Three patients (28%) required a dose reduct(diarrhea, nausea, elevated liver enzymes) areduction. 

Hale11 1998 

Study design: RCT Length of followup: 20 weeks 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement > 18y Range L: 47.8 +/- 11.5; I: 46.9 +/- 13.8; H: 50.6 +/- 10.5 

Dose: L: 0.45 g BID then adj : 0.95 g BID then adj H: 1.7 g BID then adj Concomitant medications: Cyclosporine Corticosteroids 

The risk of diarrhea and the risk of prematuradverse events were both significantly relate

Kuypers15 2003 

Study design: Case series Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Mean 49.4 +/- 13.1y 

Dose: 1 g BID Concomitant medications: Methylprednisolone Tacrolimus Daclizumab 

MMF doses were reduced by blinded investiexperienced adverse events (leucopenia, GI 
49

Table 3. Studies showing that adverse events are related to MMF dosage (continued) 

Study Population Treatment Major Findings/ Com

Maes16 2003 

Study design: Case series Length of followup: 2 years 

Organ transplanted: Kidney (Renal) Age: Mean 46 +/- 15y Range 18 – 70y 

Dose: 1.6 +/- 0.5 g/day, range 1 – 3 g/day Concomitant medications: Cyclosporine Tacrolimus Methylprednisolone 

MMF dose reduction was the only effective tlike enterocolitis. Thus, MMF (and/or MPA) m

Merkel22 2005 Study design: Retrospective Cohort Length of followup: 16 months, mean 5.7 months 

Organ transplanted: Kidney (Renal) Age: Mean 44 +/- 13.6y Range 13 – 63y 

Dose: 0.5 - 1.0 g BID Concomitant medications: Cyclosporine Prednisone Corticosteroids 

More adverse events occurred in patients treg/day (p value not given). 

Mourad33 2001 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Range 32-68y Median 49y 

Dose: 500 mg BID + adjustment for side effects Concomitant medications: Tacrolimus Corticosteroids 

MMF dose per body surface area (mg/m2) tw

higher in 31 patients (samples) who experiecompared with 47 patients (samples) who dimg/m2, p=0.02). 

van Besouw72 1999 

Study design: Case series Length of followup: 8 months 

Organ transplanted: Kidney (Renal) Age: Not reported 

Dose: 2 g/d – 1 g/day Concomitant medications: Prednisone 

Although MMF dose reduction from 2 g/day hemoglobin concentration (p=0.12), after a fg/day, the hemoglobin concentration in 20 opre-conversion (from CsA to MMF) concentrsummarized that “Not only the MMF dose bu(MPA) predose concentration correlated with 

van Gelder12 1999 

Study design: RCT Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Range L: 47.8 +/- 11.5y; I: 46.9 +/- 13.8y; H: 50.6 +/- 10.5y 

Dose: L: 16.1 ug hr/ml I: 32.2 ug hr/ml H: 60.6 ug hr/ml Concomitant medications: Cyclosporine Prednisone Corticosteroids 

Posthoc analysis showed that only the prem(and not other) adverse events was significaThis suggests that high local, non-systemic, responsible for the GI adverse events. 
50

Table 4. Studies showing that adverse events are not related to MMF dosage 

Study Population Treatment Major Findings/ 

Barbari53 2005 

Study design: Case control Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 39y Range 20 – 67y 

Dose: 1 g BID range 1 - 2.5 g/day Concomitant medications: Cyclosporine Prednisone 

There was a poor associatio(primarily rejection, but also indicator of immune responspredose MPA concentrations 

Borrows14 2006 

Study design: Case series Length of followup: 38 months 

median 25 months 

range 13-38 months 

Organ transplanted: Kidney (Renal) Age: Mean 46 +/- 9y Range 37 – 55y 

Dose: 750 mg – 2 g/day Concomitant medications: Tacrolimus Methylprednisolone Prednisone Corticosteroids Ganciclovir (for 3 months) Co-Trimoxazole (for 6 months_ Isoniazid and Puridoxine (used in indo-asians and those with previous TB) Basiliximab or Daclizumab (79 patients) 

In multivariate analysis, total significantly associated with or acute rejection, but was with anemia and MMF-assoand 0.003, respectively) 

Heller77 2007 

Study design: Prospective cohort Length of followup: 12 months

Organ transplanted: Kidney (Renal) Age: Mean 53.4y

Dose: Fixed dose group: 1 g BID, Concentrationcontrolled group: target concentration of 30-60 mg*h/L Concomitant medications: Cyclosporine Tacrolimus

Mean MMF daily doses were between patients with diarrhe

Abbreviations: AUC=Area-under-the-concentration-time curve, AZA=Azathioprine, BID=Twice Daily, Cmax=Maximum Serum or Plasma ConcentratioPlasma Concentration, CsA=Cyclosporin A, MMF=Mycophenolate Mofetil, MPA=Mycophenolic Acid, NR= Not Reported, PSL=Prednisolone, RCT=

Trial, Tmax=Mean Time to Maximum Concentration, y=Years
51

Table 4. Studies showing that adverse events are not related to MMF dosage (continued) 

Study Population Treatment Major Fin

Hubner56 2000 Study design: Case series Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 45y 

Dose: 1.0 g BID Concomitant medications: Cyclosporine A Methylprednisolone 

No significant difference was patients with adverse events p>0.05) 

Kaplan21 1999 

Study design: Case series Length of followup: >2 weeks 

Organ transplanted: Kidney (Renal) Age: Range 46.7 +/- 9.2y for chronic renal subjects, 43.3 +/- 8.6y for renal patients without chronic insufficiency 

Dose: 1.75 +/- 0.3 g/day Concomitant medications: Not reported 

No p values were given, but between MMF dose and advand adverse events 

Orlando61 2006 Study design: Case series Length of followup: mean 31.5 +/- 6.1 months 

Organ transplanted: Liver Age: Mean 60.1y Range: 35 – 67y 

Dose: 250 mg BID increased weekly by 500 mg to dose of 1500 mg/d Concomitant medications: Cyclosporine Tacrolimus 

All adverse events occurred case of (leukopenia and thro1 g. 

Satoh35 2005 

Study design: Prospective Cohort Length of followup: 28 days 

Organ transplanted: Kidney (Renal) Age:Mean AZA: 37.9 +/- 11.5y MMF: 44.3 +/- 11.6y 

Dose: 1.0 – 2 g/day Concomitant medications: Tacrolimus Methylprednisolone Prednisone 

Neither MMF dose per bodywrespectively) nor MPA AUC0-

were significantly different in to those without 

Sugioka76 2006 

Study design: Case series Length of followup: 28 days 

Organ transplanted: Kidney (Renal) Age: Range MPA group: 7 – 69y PSL group: 11 – 66y 

Dose: MPA group: 1000 or 1500 mg/day Concomitant medications: Cyclosporine A Tacrolimus Prednisolone 

No significant differences weparameter (AUC0-9, Cmax, Tma

dose/kg) between patients wleucopenia or diarrhea 
52

Table 4. Studies showing that adverse events are not related to MMF dosage (continued) 

Study Population Treatment Major Fin

Takahashi31 1995 

Study design: Non randomized controlled trial Length of followup: 12 weeks 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement ≥16y 1000 mg/d: Mean 37.7 +/- 6.3y 2000 mg/d: Mean 38.5 +/- 12.2 y 3000 mg/d: Mean 41.0 +/- 10.3 y 

Dose: 1000, 2000, or 3000 mg/day Concomitant medications: Cyclosporine Steroids (no description) 

The incidences of adverse ev3000 mg MMF dose groups wrespectively (p> 0.05) 

van Besouw72 1999 

Study design: Case series Length of followup: 8 months 

Organ transplanted: Kidney (Renal) Age: NR 

Dose: 2 g/d – 1 g/d Concomitant medications: Prednisone 

MMF dose reduction from 2 ghemoglobin concentration (preduction to 1 g/day, the hem

patients had reached pre-conconcentrations (p=0.75). The the MMF dose but also the mconcentration correlated with 

Wang51 1998 

Study design: RCT Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Range 35-59y 

Dose: Group 1. 1.0 g BID Group 2. 0.75 g BID Concomitant medications: Cyclosporine Corticosteroids Methylprednisolone Prednisone 

No significant differences we

AUC0-12 for patients in the MM

One patient in the MMF 1 g BBID group had an acute rejecreported that “There were no effects between group 1 and 
53

Table 5. Association of MPA monitoring with free vs total MPA and albumin 

Study Associations 

Atcheson13 2005 • Urea, creatinine correlate with free fractions of MPA, MPAG 

• Albumin correlate negatively with free fractions of MPA, MPAG • MPA, fMPA unrelated to rejection • fMPA AUC (but not total) higher with thrombocytopenia, leukopenia, infection than without 

Borrows14 2006 • MPA concentrations correlate with anemia, leukopenia, diarrhea, viral infections 

• MPA concentrations inversely correlate with rejection within 1st month 

• hypoalbuminemia, renal impairment correlate with hemotoxicity • No association with MPA – platelets, bacterial infections • 1.60 mg/L MPA early post-transplant discriminates rejecters/non-rejecters 

• 2.75 mg/L MPA later post-transplant discriminates toxicity/no toxicity. 

Cattaneo18 2001 • Creatinine, creatinine clearance correlates with MPA C0 and AUC, renal function better with AUC > 40 

• Free fraction MPA, not total, correaltes with RBC and leukocytes • No difference in rejections between AUC > or < 40 

DeNofrio19 2000 • No difference in MPA C0 between rejection grades 

• MPA AUC, fMPA AUC smaller in grade 2/3 vs. 0 or 1, no difference free vs. total • No significant difference MPA C0 between grade 2/3 vs. 0 or 1 

Kaplan21 1999 •Free fraction, fMPA AUC, MPAG, but not MPA AUC increased in renal failure 

• Hint at increase of leukopenia (but not other adverse events.) with fMPA 

Kuypers15 2003 • No relation MPA, fMPA, AcMPAG, MPAG – efficacy, adverse events 

• Intra-patient correlates AcMPAG, MPAG, AcMPAG/MPA – anemia • fMPA AUC, free fraction MPA, fMPA inverse correlation with GFR • AcMPAG AUC negative correlation with creatinine clearance (• fMPA AUC correlates with MPAG AUC) 

Maes16 2003 • MPA, fMPA inverse correlation with colonic transit time, no difference free and total Shaw20 2000 • MPA AUC, fMPA AUC, MPA, MPAG not associated with diarrhea 

• fMPA AUC higher in 5 patients with leukopenia and IRF than in 8 IRF patients without leukopenia (not signif

• MPA C-max, AUC smaller in IRF vs. non-IRF on day 4, NS on day 90 

• MPA clearance higher in IRF vs. non-IRF on day 4, NS on day 90 • No difference free fraction AUC in IRF vs non on days 4 and 90 

Weber17 2002 • MPA AUC associated with rejection risk; 33.8 mg*h/L: 75% sensitivity, 64% specificity 

• MPA C12 1.2 mg/L discriminates rejectors early post-tx, 83% sensitivity, 64% specificity 

• fMPA AUC, not MPA AUC, associated with leukopenia, infection 

• Albumin, GFR correlated with MPA AUC 1 wk post transplant, not later 

Abbreviations: AcMPAG=Acyl Glucuronide Metabolite of Mycophenolic Acid AUC=Area-under-the-concentration-time curve, C0=Predose Trough B

Cmax=Maximum blood or Plasma Concentration fMPA=Free Mycophenolic Acid, GFR=Glomerular Filtration Rate, IRF=Impaired Renal Function, M

MPAG=Mycophenolic Acid Glucuronide, NS=Not Significant; RBC=Red Blood Cells 
54

Table 6. Association of MPA outcomes with metabolites or genes 

Study Associations 

Behrend25 1997 MPA, MPAG – renal function (MPA not correlation., MPAG inverse correlation., data not shown), AE/R (no a

shown) 

Bunchman23 2001 MPA, MPAG – AE/R, No associations found, but data not shown Cantin58 2002 MPA – rejection Cattaneo18 2001 MPA – rejection, kidney function; fMPA, MPA – AE Filler73 1998 MPA – diarrhea Gajarski44 2004 MPA – rejection Gonzalez-Roncero 109

2005 

MPA, fMPA, MPAG, C0 and AUC – renal function: all higher in renal insufficiency than normal renal function

Johnson111 1999 MPA, MPAG AUC correlation - creatine; MPA AUC correlation – albumin Kaplan21 1999 fMPA, MPAG AUC incr. in renal failure vs. function, MPA AUC same Kuypers15 2003 MPA, metabolites – AE/R, lab outcomes 

Intra patient: No association MPA, fMPA, AcMPAG, MPAG C0, Cmax, AUC – rejection, diarrhea, leukopenia 

Higher AcMPAG C0, MPAG C0, AcMPAG/MPA, but not MPA in anemia (n=19) vs. not MPA, fMPA, MPAG, AcMPAG Cmax or AUC: no difference between anemia (n=29) or leucopenia (n=12) or n

Inter-patient: No association MPA, fMPA, AcMPAG, MPAG C0, Cmax, AUC – rejection, diarrhea, leukopenia, 

shown); diarrhea, rejection not captured by AUCs, Cmax (too rare) 

Correlation with GFR: MPAG C0: r2 = -0.791 

MPAG AUC: r2 = -0.709 

fMPA C0: r2 = -0.791 

fMPA AUC: r2 = -0.477 

AcMPAG C0: r2 = -0.781 

AcMPAG AUC: r2 = -0.505 

MPA C0: r2 = 0.399 

MPA AUC: r2= -0.039; all p<0.001 

Maes16 2003 MPA, metabolites. – fecal fat loss 

Correlation fecal fat loss MPAG, AcMPAG, probably not MPA 

Mandla R 38 2006 MPA – rejection; fMPA – albumin, kidney function Merkel U 22 2005 Linear correlation. MPA C0 – creatine, MPAG C0 – creatine stronger correlation 

Slight linear correlation MPA – protein, not MPAG – protein Elevated transaminases (3 patients): MPA, MPAG concentrations similar to those without elevated transamTwo CMV infections: MPA, MPAG in 1st patient similar to those in patients without CMV; MPA in second (re

patient higher than in first CMV patient One diarrhea, no correlation to concentrations 4 rejections in 35 patients, 2 MPA concentrations in 2 acute rejections 

Abbreviations: AcMPAG=Acyl Glucuronide Metabolite of Mycophenolic Acid, AE=Adverse Events, AE/R=Adverse/Rejection, AUC=Area-under-the

C0=Predose Trough Serum or Plasma Concentration, Cmax=Maximum Serum or Plasma Concentration, CMV=Cytomegalovirus, CyA=Cyclosporine, 

Acid, GFR=Glomerular Filtration Rate, IRF=Impaired Renal Function, MPA=Mycophenolic Acid, MPAG=Mycophenolic Acid Glucuronide, ROC= RCharacteristic, TAC=Tacrolimus
55

Table 6. Association of MPA outcomes with metabolites or genes (continued) 

Study Associations 

Mogera115 1998 MPA, MPAG AUC inverse correlation – GFR Morgera116 1998 MPAG AUC inverse correlation. - GFR, no difference for MPA Naito108 2006 Positive correlation MPA, MPAG C0 - creatine, stronger with CyA than Tac Naesens79 2006 MPA – liver and renal function, genes; genes - AE/R (diarrhea) Pawinski64 2006 MPA – rejection (ROC), renal function Satoh30 2006 MPA – rejection, genes; genes - AE/R (diarrhea) Shaw20 2000 MPA, fMPA, MPAG – diarrhea, renal function 

No association MPA, fMPA, MPAG – diarrhea MPAG, not MPA C0 higher in IRF 

Shaw113 1998 free fraction, MPAG, creatinine decrease with time, MPA increases but cannot be modeled Sumethku32 2005 MPA – AE/R Tsaroucha24 2000 MPA, MPAG – rejection (no correlation) Weber110 1999 fMPA, MPAG AUC – GFR (inverse correlation), MPA AUC increases with time, fMPA, MPAG AUCs consisteWeber112 1998 fMPA, MPAG, not MPA inverse correlation with GFR 
56

Table 7. Studies showing some relationship between rejection and method of MPA monitoring 

Study Population Treatment Major Finding

Armstrong27 2001 

Study design: Case series Length of followup: 70 days 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement pediatric Mean NR 

Dose: 600 mg/m2 BID 

Concomitant medications: Cyclosporine Methylprednisolone 

MPA AUC cut off of 29.5 mgrejection had a diagnostic sdiagnostic specificity of 79.4

Hale11 1998 

Study design: RCT Length of followup: 20 weeks 

Organ transplanted: Kidney (Renal) Age:Inclusion requirement > 18y Range L: 47.8 +/- 11.5y; I: 46.9 +/- 13.8y; H: 50.6 +/- 10.5y 

Dose: L: 0.45 g BID then adjust; I: 0.95 g BID then adjust; H: 1.7 g BID then adjust Concomitant medications: Cyclosporine Corticosteroids 

According to logistic regressvalues of 15, 25, and 40 mg50%, 75%, and 90% of max(with a 4% change in efficacchange in AUC at the midpoUnivariate logistic regression proven rejection vs. MPA AUthe first 3 assessments were the later 6 assessments wer

by LSS of C0,C20min,C40min,C7

Hazzan28 2005 

Study design: RCT Length of followup: 1 year 

Organ transplanted: Kidney (Renal) Age: Mean CsA 42.5 +/- 12.1 MMF 45.1 +/- 11.2 

Dose: CsA group MMF dose = 1.93 +/- 0.2 g/day then withdrawn to 0, MMF group MMF dose = 1.99 +/- 0.1 g/day Concomitant medications: Cyclosporine Prednisone 

MPA AUC (a 50 mg·h/L cut 

concentration, was associatemultivariate analysis. Author“needs to be confirmed by fu

Lu29 2005 

Study design: Non Randomized Clinical Trial Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 40.0 +/- 12.0y 

Dose: mean 58.0 +/- 10.0 kg Concomitant medications: Cyclosporine Prednisone Tacrolimus 

MPA AUC was lower in the pcompared to those without Aμg·h/mL, p=0.038). 

Mourad33 2001 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Range 32-68y Median 49y 

Dose: 500mg BID + adjustment for side effects Concomitant medications: Tacrolimus Corticosteroids 

MPA measurements at the tpatients (5.8%) at a fixed dowere: MPA AUC of 37.7, 24.

(not much data) 

Abbreviations: AR=Acute rejection, AUC=Area-under-the-concentration-time curve, BID=Twice Daily, C0=Predose Trough Serum or Plasma ConcentEMIT=Enzyme-Multiplied Immunoassay Technique, ECMPS=Enteric Coated Mycophenolate Sodium, H=High, HPLC=High-Performance Liquid ChrI=Intermediate, L=Low, LSS=Limited Sampling Strategy, MMF=Mycophenolate Mofetil, MPA=Mycophenolic Acid, NR=Not Reported, RCT=Random

y=Years
57

Table 7. Studies showing some relationship between rejection and method of MPA monitoring (continued) 

Study Population Treatment Major 

Satoh30 2006 

Study design: Case series Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 41.2 +/- 2.1y Range 21 – 66y 

Dose: 2 g/day Concomitant medications: Tacrolimus Methylprednisolone Corticosteroids 

Mean MPA without AR μg·h/L (day

μg·h/mL (ni(p<0.02). 

Sumethkul32 2005 

Study design: Case series Length of followup: 3-8 months 

Organ transplanted: Kidney (Renal) Age: Mean 39 +/- 9y 

Dose: 720 mg BID Concomitant medications: Cyclosporine Prednisone 

Only very wpurpose of sdelivery of Mcorrelate MPhealth outcoAUC = 52, 1

no evidence (MPA AUC 

borderline a

Takahashi31 1995 

Study design: Non randomized controlled trial Length of followup: 12 weeks 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement ≥16y 1000 mg/d: Mean 37.7 +/- 6.3y 2000 mg/d: Mean 38.5 +/- 12.2y 3000 mg/d: Mean 41.0 +/- 10.3y 

Dose: 1000, 2000, or 3000 mg/day Concomitant medications: Cyclosporine  steroids (no description) 

Rejection g

(1/12 patien

MPA AUC (

Weber26 2002 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Mean 11.8y Range 3.2 - 16.0y 

Dose: 600 mg/m2 twice a day to a maximum of 2 g/day Concomitant medications: Cyclosporine A Methylprednisolone 

AUC was abbetween paacute rejectmg·h/L had 

80% and a d57%; AUC (

Weber17 2001 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Range 2.2-17.8y 

Dose: 600 mg/m2 BSA twice a day up to 2 g/day maximum Concomitant medications: Cyclosporine A 

MPA AUC wbetween paacute rejectmg·h/L had 

75% and a d
58

Table 7. Studies showing some relationship between rejection and method of MPA monitoring (continued) 

Study Population Treatment Major 

Methylprednisolone 64.3%. 

van Gelder12 1999 

Study design: RCT Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Range L: 47.8 +/- 11.5y; I: 46.9 +/- 13.8y; H: 50.6 +/- 10.5y 

Dose: L: 16.1 ug hr/ml I: 32.2 ug hr/ml H: 60.6 ug hr/ml Concomitant medications: Cyclosporine Prednisone Corticosteroids 

At the 3 targ16.1; interm60.6 mg.h/Lproven acut14.9%, and (p=0.043). Nwere exceewas a signifmedian ln Mproven acut
59

Table 8. Studies showing some relationship between rejection and method of MPA monitoring. Limited sampling strategies – Pre

Study Population Treatment Major Findings

Armstrong27 2001 

Study design: Case series Length of followup: 70 days 

Organ transplanted: Kidney (Renal) Age: NR 

Dose: 600 mg/m2 BID 

Concomitant medications: Cyclosporine Methylprednisolone Prednisone 

MPA C0 cut off was 1.0 mg/L 

rejection had a diagnostic sespecificity of 64.5%; MPA C0 

(EMIT) 

Braun 39 1998 

Study design: Prospective Cohort Length of followup: median 280 days (19-585) 

Organ transplanted: Kidney (Renal) Liver Age: NR 

Dose: 30-40 mg/kg/day Concomitant medications: Tacrolimus 

Weak supporting data: All 6 rejection had low MPA predomg/L) 

Brusa41 2000 

Study design: Prospective Cohort Length of followup: >12 months 

Organ transplanted: Kidney (Renal) Age: Range for 18 patients 13-58y; 5 patients 35-56y 

Dose: 250 to 1000 mg/day BID Concomitant medications: Cyclosporine Corticosteroids 

Very weak supporting data fmonitoring: The authors repointerstitial rejection were obstransplanted patients having below 2 μg/mL” but no data 

Filler46 2000 

Study design: Case series Length of followup: 6.2 +/- 2.7y (2.3-11.8) 

Organ transplanted: Kidney (Renal) Age: Mean 17.2y +/- 4.2 SD y 

Dose: 600 mg/m2 BID Concomitant medications: Cyclosporine  Steroids 

Weak supportive data: Othevery low MPA predose concprovided) who experienced rejection episode 566 days ano patient experienced rejec

Gajarski44 2004 

Study design: Case series Length of followup: NR 

Organ transplanted: Heart (Cardiac) Age: Mean 15.4 +/- 9.5 years Range 1 month - 33 years 

Dose: average 1206.8 +/- 301.9 mg/m2

Concomitant medications: Cyclosporine Tacrolimus 

Endomyocardial biopsy grad

with significantly lower MPA (1.05 vs. 2.3, p<0.01) compa1B. Grade > 2 also occurred frequently with MPA concen(p=0.03) 

Abbreviations: AR=Acute rejection, AUC=Area-under-the-concentration-time curve, BID=Twice Daily, C0=Predose Trough Serum or Plasma ConcentEMIT=Enzyme-Multiplied Immunoassay Technique, H=High, HPLC=High-Performance Liquid Chromatographic, I=Intermediate, L=Low, LSS=Limi

MMF=Mycophenolate Mofetil, MPA=Mycophenolic Acid, NR=Not Reported, RCT=Randomized Controlled Trial, ROC=Receiver Operating CharacteTAC=Tacrolimus; TID=Three times per day; SD= Standard Deviation, y=Years
60

Table 8. Studies showing some relationship between rejection and method of MPA. Limited sampling strategies – Predose (C0, C

Study Population Treatment Major Findings

Hesse45 2001 

Study design: Case series Length of followup: mean 10.1 months 

Organ transplanted: Heart (Cardiac) Age: NR 

Dose: 1500 mg BID + dose reductions on clinical symptoms Concomitant medications: Tacrolimus Prednisone CsA 

Median MPA predose concesignificantly lower in patientcompared to patients withouvs. 1.76 mg/L, p=0.015) 

Krumme47 1998 Study design: Case series Length of followup: 2 months 

Organ transplanted: Kidney (Renal) Age: Range 46 +/-11y 

Dose: 1 g BID Concomitant medications: Cyclosporine Methylprednisolone 

Mean MPA predose (C0 or t

were significantly lower in pcompared with those withoup<0.005) 

Lu48 2006 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Mean 34.1 +/- 7.1y Range 18 to 64y 

Dose: weight directed dosage (50 kg: 2.0 g/day) starting 2 days before transplantation Concomitant medications: Cyclosporine CsA, Neoral  steroids 

Group A: n=239 (66.9%), no acute rejections, mean MPA 

mg/L group B: n=100 (28.0%mean MPA C0 1.5903 +/- 0n=18 (5.0%), an acute rejec

0.6057 +/- 0.2338 mg/L (p<<0.001, between A and B, A respectively. Although ROC significant correlations betw

events (toxity and rejection)high degree of diagnostic seor specificity (74.7 to 84.7%authors. Note that MPA C0 significantly correlated (r=0.study. Also note Lu120 conta

statistical significance same 

Mandla38 2006 Study design: Non randomized controlled trial Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Mean 54y Range 19 -77y 

Dose: 1 g BID in combined kidney plus pancreas transplant patients 1 g TID Concomitant medications: Cyclosporine Tacrolimus Methylprednisolone Prednisone 

Acute rejection rate was 44attained > 1 μg/mL (i.e., the predose concentration) and concentrations < 1 μg/mL (p paradoxical finding suggestthe relation between MPA c
61

Table 8. Studies showing some relationship between rejection and method of MPA. Limited sampling strategies – Predose (C0, C

Study Population Treatment Major Findings

Meiser7,8 1999 

Study design: Non randomized controlled trial Length of followup: Phase 1: 696 +/- 62d (606-790) Phase 2: 436 +/- 88d (175-562) 

Organ transplanted: Heart (Cardiac) Age: Inclusion requirement Phase 1 & 2: >18y Range Phase 1: 50.6 +/- 11.4y (18-64); Phase 2: 54.1 +/- 8.9y (21-66) 

Dose: 1 g BID Concomitant medications: Tacrolimus Prednisone Prednisolone 

In Phase I, the mean MPA ppatients who had no episodrejection episodes, and 3 re3.6 vs. 2.2 vs. 1.4 μg/mL (p Phase 2, 3 patients (all of wone rejection episode each) concentrations of 0.7, 1.3, athere were other confoundinalso suggested that mean Mconcentrations > 3 μg/mL rejection, but no details wer

Mourad33 2001 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Range 32-68y Median 49y 

Dose: 500 mg BID + adjustment for side effects Concomitant medications: Tacrolimus Corticosteroids 

MPA measurements at the 3 patients (5.8%) at a fixed daily were: MPA C0 of 1.86, 

Pawinski43 2006 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Mean 48y Range 17 – 62y 

Dose: 1 g BID Concomitant medications: Cyclosporine Tacrolimus Prednisone 

C0 cut off of 0.8 mg/L had a 

59.3% and diagnostic specithan Cmax but worse than AU

C0,C0.5, and C2) 

Satoh30 2006 

Study design: Case series Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 41.2 +/- 2.1y Range 21 – 66y 

Dose: 2 g/day Concomitant medications: Tacrolimus Methylprednisolone Corticosteroids 

Mean MPA predose concenand without AR were 0.71 aand 1.03 and 3.22 μg/mL (n(p=0.001) 

Tredger40 2004 

Study design: Prospective Cohort Length of followup: 2 years (Feb 1 2000 - Feb 28 2002) 

Organ transplanted: Liver Age: Mean adults median: 50.1y, children median: 3.5 years Range adults: 16.9 - 71.8y, children: 0.3 - 19.5y 

Dose: adults: 500 mg BID then increased, children: 5 mg/kg BID then increased Concomitant medications: Cyclosporine Tacrolimus 

Optimal efficacy and fewest population at a predose MP1 mg/L. Figure 1b within this rejection (95%CI) increased fold (1.92-3.22) and 1.6-fold MPA concentrations less th(p=0.003, 0.002 and 0.058)
62

Table 8. Studies showing some relationship between rejection and method of MPA. Limited sampling strategies – Predose (C0, C

Study Population Treatment Major Findings

Weber26 2002 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Mean 11.8y Range 3.2 - 16.0y 

Dose: 600 mg/m2 BID to a 

maximum of 2 g/day Concomitant medications: Cyclosporine Methylprednisolone 

C0 and C12 were able to dis

patients with and without ac

of 1.2 mg/L had a diagnostidiagnostic specificity of 60%

mg/L.

van Gelder12 1999 

Study design: RCT Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Range L: 47.8 +/- 11.5y; I: 46.9 +/- 13.8y; H: 50.6 +/- 10.5y 

Dose: L: 16.1 μg hr/ml I: 32.2 μg hr/ml H: 60.6 ug hr/ml Concomitant medications: Cyclosporine Prednisone Corticosteroids 

There was a significant relaC0 and biopsy-proven acute 

Yamani42 2000 

Study design: Retrospective Cohort Length of followup: 179 +/- 52 days 

Organ transplanted: Heart (Cardiac) Age: Mean 36 +/- 14y 

Dose: 2 g/day Concomitant medications: Cyclosporine Tacrolimus Prednisone 

In the first year post-transplrejection was significantly losamples with MPA predose compared with those < 2 mmonths, p=0.05 and 4.2 vs. p=0.05). When CSA or TAC “therapeutic”, the incidence significantly lower at MPA p> 2 mg/L compared with tho

14.4%, p=0.005)
63

Table 9. Studies showing some relationship between rejection and method of MPA monitoring. Limited sampling strategies - 2h 

Study Population Treatment Major Findings

Kiberd57 2004 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Mean 48 +/- 13y 

Dose: 2 g/day fixed Concomitant medications: Prednisone Neoral 

Day 3 MPA C2 significantly (

rejection. 

Abbreviations: MPA=Mycophenolic Acid, y=Years
64

Table 10. Studies showing some relationship between rejection and method of MPA. Limited sampling strategies - Other 

Study Population Treatment Major Findings/ 

DeNofrio19 2000 

Study design: Case series Length of followup: 310 +/- 278 days 

Organ transplanted: Heart (Cardiac) Age: Mean 53 +/- 10y 

Dose: 1g BID Concomitant medications: Cyclosporine 

Lower MPA AUC (as predicted C0,C20min,C40min,C75min, and C12

cardiac allograft rejection. Spevalues were significantly lower 2/3 than in patients with Grade mg·h/L, p< 0.05) 

Kiberd57 2004 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age:Mean 48 +/- 13y 

Dose: 2 g/day fixed Concomitant medications: Prednisone Neoral 

Day 3 MPA AUC (based on LS

significantly predicted later rejebest cutoff point was an AUC cmg*h/L (sensitivity 82%, specifpredictive value 89% and posit

Kuriata-Kordek54 2002 

Study design: Case control Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement group I: 38.12 +/- 9.5y, group II: 38.52 +/- 9.21y 

Dose: 2.0 g/dayay Concomitant medications: Cyclosporine Prednisone 

C40min values were significantly 

with acute rejection compared rejection (6.47 vs. 18.5 mg/L, p

Le Meur10 2007 

Study design: RCT Length of followup: 12 months 

Organ transplanted: Kidney Age: Fixed dose group 49 +/- 13y Concentration-controlled group: 50 +/- 14y 

Fixed dose group: 1g BID; Concentration-controlled group: Days 1-7, 1g BID, then dose to target AUC of 40 mg*h/L Concomitant medications: Cyclosporine Methylprednisolone Basiliximab Trimethoprimsulfamethoxazole 

Incidence of treatment failure, endpoint, was significantly lowcontrolled group (that used LS

developed by Bayesian metho40 mg*h/L) compared with the vs. 47.7%, p=0.03); percentag(12.3% vs. 30.7%, p=0.01) and rejection (7.7% vs. 24.6%) werconcentration-controlled group

Okamoto49 2005 Study design: Non randomized controlled trial Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 38 +/- 14y 

Dose: 25 mg/kg initially, then adjusted afterwards Concomitant medications: Cyclosporine n=35 Tacrolimus n=32 

MPA AUC0-9 was significantly l

compared with those without (2

p=0.04085) 

Abbreviations: AR=Acute rejection, AUC=Area-under-the-concentration-time curve, BID=Twice Daily, BSA=Body Surface Area, C0=Predose Trough 

Concentration, Cmax=Maximum Serum or Plasma Concentration, CsA=Cyclosporin A, LSS=Limited Sampling Strategy, MMF=Mycophenolate Mofetil

NR=Not Reported, RCT=Randomized Controlled Trial, y=Years
65

Table 10. Studies showing some relationship between rejection and method of MPA monitoring. Limited sampling strategies - O

Study Population Treatment Major Findings/ 

Pawinski64 2006 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Range 17 – 62y 

Dose: 0.5 - 2 g/day Concomitant medications: Cyclosporine Tacrolimus Prednisone 

AUC (based on LSS of C0, C0

acute rejection of 27.5 mg·h/L 

sensitivity of 81.2% and a diag93.4% (i.e., best predictor of a

Pawinski43 2006 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Mean 48y Range 17 – 62y 

Dose: 1 g BID Concomitant medications: Cyclosporine Tacrolimus Prednisone 

AUC (based on LSS of C0, C0

mg·h/L had a diagnostic sens

diagnostic specificity of 91.7% predose and Cmax) 

Pillans59 2001 

Study design: Case series Length of followup: 1 month 

Organ transplanted: Kidney (Renal) Age: Range 21-65y 

Dose: 2 g/day Concomitant medications: Cyclosporine Prednisone 

MPA AUC (as predicted by a L

C6) was significantly lower in pbiopsy-proven rejection comparejection (27.6 vs. 35.1 mg·h/L

patients (29%) with an MPA A

rejection episode but 8 of 13 pMPA AUC <30 mg·h/L experie

Weber63 2006 

Study design: Case series Length of followup: 6 months posttransplant suspension trial: 36 months 

Organ transplanted: Kidney (Renal) Age: Range German study: 3.17-16.0y, Suspension trial: 1.0-16.0y 

Dose: German study: 600 mg/m2 BSA up to 2 g/day 

suspension trial: 600 mg/m2

body surface area BID (up to 1000 mg BID), corresponding to 1 g MMF BID in adult renal transplant recipients Concomitant medications: Cyclosporine CsA microemulsion: German study and suspension trial Methylprednisolone German study Prednisone suspension trial Corticosteroids 

AUC (based on LSS of C0, C0

discriminate patients with acutwith no rejection; AUC cut off prognostic sensitivity of 66.7% specificity of 61.9% 
66

Table 10. Studies showing some relationship between rejection and method of MPA monitoring. Limited sampling strategies - O

Study Population Treatment Major Findings/ 

Weber26 2002 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Mean 11.8y Range 3.2-16.0y 

Dose: 600 mg/m2 BID to a 

maximum of 2 g/day Concomitant medications: Cyclosporine A Methylprednisolone 

AUC (based on LSS of C0, C75

discriminate between patients rejection 

Weber17 2001 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Range 2.2-17.8y 

Dose: 600 mg/m2 BSA BID up 

to 2 g/day max Concomitant medications: Cyclosporine A Methylprednisolone 

AUC (based on LSS of C0, C75

discriminate between patients rejection 
67

Table 11. Studies showing no relationship between rejection and method of MPA monitoring 

Study Population Treatment Major Findings/ 

Kuypers36 2004 

Study design: Case series Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Median 51.5y 

Dose: 0.5 g BID or 1 g BID Concomitant medications: Tacrolimus Methylprednisolone Daclizumab 

Same study as 52 (Prospective 

MPA AUC (56.5 vs. 46 mg.h/Lsignificantly lower between patexperienced acute rejection anIncidence of acute rejection wasignificantly higher for patients target tacrolimus AUC of 150 n45 mg.h/L by Day 7 compared (26.3% vs. 7.7%, p=0.07). Not

obtained on Day 7, a 2-h AUC AUC at months 3,6, and 12 (thused to predict AUC0-12) 

Mourad37 2000 

Study design: Case series Length of followup: 12 weeks 

Organ transplanted: Kidney (Renal) Age: Mean 46y Range 33-57y 

Dose: 1 g BID Concomitant medications: Cyclosporine Prednisolone 

MPA AUC data were similar wug *h/mL associated with rejecuneventful outcomes, respectivprovided) 

Reggiani34 2001 

Study design: RCT Length of followup: mean 31 +/- 7 months 

Organ transplanted: Liver Age: Mean A: 49.7 +/- 4.6y, group B: 50.4 +/- 8.9y 

Dose: 750 mg BID 1st month, 500 mg BID > 1 month Concomitant medications: Tacrolimusgroup A and B Methylprednisolone group B Prednisone group B 

No difference in MPA AUC wawith acute rejection compared not provided) 

Satoh35 2005 

Study design: Prospective Cohort Length of followup: 28 days 

Organ transplanted: Kidney (Renal) Age: Mean AZA: 37.9 +/- 11.5y MMF: 44.3 +/- 11.6y 

Dose: 1.0 – 2 g/day Concomitant medications: Tacrolimus Methylprednisolone Prednisone 

There was no significant differepatients with AR compared to tvs. 59.5 μg·h/L, p=0.081) 

Abbreviations: AR=Acute rejection, AUC=Area-under-the-concentration-time curve, AZA=Azathioprine, BID=Twice Daily, MMF=Mycophenolate M

Acid, RCT=Randomized Controlled Trial, y=Years
68

Table 12. Studies showing no relationship between rejection and method of MPA monitoring. Limited sampling strategies – Pred

Study Population Treatment Major Findings/ 

Barbari53 2005 

Study design: Case control Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 39y Range 20 – 67y 

Dose: 1 g BID range 1 - 2.5 g/day Concomitant medications: Cyclosporine Prednisone 

There was a poor association (primarily rejection, but also lymindicator of immune responsiveMPA concentrations. (r2=0.080

respectively; Fig. 2, 3 and 4 , p

Behrend 25 1997 Study design: RCT Length of followup: at least 1 year 

Organ transplanted: Kidney (Renal) Age: NR 

Dose: 2 g/day or 3 g/day; dose per body weight was 22 to 54 mg/Kg; mean 83 mg/kg + - 8.4 body weight Concomitant medications: Cyclosporine Corticosteroids 

 Very very weak supportive da“there is no clearcut relationshconcentrations and rejection, ainfections” but provide no datainterindividual variability in MP

predose) concentrations is “by correlation to ...dose...” but do 

Bilbao62 2006 Study design: Case series Length of followup: mean 39 + - 20 months; range 3 to 72 months 

Organ transplanted: Liver Age: Mean 59 +/ - 6y 

Dose: Initial dose of 500 mg/12h; reaching dose of 1 g each 12h for 2 weeks 

Concomitant medications: Cyclosporine Tacrolimus 

 The authors stated that “We h

correlation between MMF predthe occurrence of rejections” bsubstantiate this statement 

Cantin58 2002 

Study design: Case series Length of followup: 1 year 

Organ transplanted: Heart (Cardiac) Age: Mean 54.4 +/- 14y Range 22–72y 

Dose: Tac group: 1810 mg/day +/- 817, CsA group: 2447 +/- 896 Concomitant medications: Cyclosporine Tacrolimus Corticosteroids 

No significant difference was oof overall rejection or high-gradpatients with MPA predose conand those with MPA concentraboth episodes of high grade (3patients with MPA concentratioauthors conclude that “There dbenefit in continued monitoring acid concentrations beyond the transplantation.” 

Abbreviations: AR=Acute rejection, ATG=Anti-Thymocyte Globulin, ATS=Anti-Tserum, AUC=Area-under-the-concentration-time curve, BID=Twice 

Area, C0=Predose Trough Serum or Plasma Concentration, Cmax=Maximum Serum or Plasma Concentration, Cmin=Minimum Serum or Plasma Concent

H=High, I=Intermediate, MMF=Mycophenolate Mofetil, MPA=Mycophenolic Acid, NR=Not Reported, RCT=Randomized Controlled Trial, SIR=Siro

y=Years
69

Table 12. Studies showing no relationship between rejection and method of MPA monitoring. Limited sampling strategies – Pre

(continued) 

Study Population Treatment Major 

DeNofrio19 2000 

Study design: Case series Length of followup: 310 +/- 278days 

Organ transplanted: Heart (Cardiac) Age: Mean 53 +/- 10y 

Dose: 1 g BID Concomitant medications: Cyclosporine 

MPA C0 in G

rejection (0.*note that apositive findnot statistica

Dipchand55 2001 

Study design: Retrospective Cohort Length of followup: 8 weeks 

Organ transplanted: Heart (Cardiac) Age: Range 29days-23.5y Median 6.3y 

Dose: various: 15-159 mg/kg Concomitant medications: Cyclosporine (A or neoral) Tacrolimus Corticosteroids azathiaprine ATG OKT3 (Monoclonal Antibody) ATS 

A therapeutconcentratio3 μg/mL. In transplant thepisodes in concentratiorejection. Thepisodes in therapeutic patients with authors statconcentratiothis is not su

Hale11 1998 

Study design: RCT Length of followup: 20 weeks 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement > 18y Range: L: 47.8 +/- 11.5 y, I: 46.9 +/- 13.8y, H: 50.6 +/- 10.5y 

Dose: L: 0.45 g BID then adjusted  I: 0.95 g BID then adjusted  H: 1.7 g BID then adjusted Concomitant medications: Cyclosporine Corticosteroids 

In bivariate analysis, bioMPA C0 wa

Hazzan28 2005 

Study design: RCT Length of followup: 1 year 

Organ transplanted: Kidney (Renal) Age: Mean CsA group 42.5 +/- 12.1y MMF group 45.1 +/- 11.2y 

Dose: CsA group MMF dose = 1.93 +/- 0.2 g/day then withdrawn to 0, MMF group MMF dose = 1.99 +/- 0.1 g/day Concomitant medications: Cyclosporine Prednisone 

MPA predosassociated wmultivariate 
70

Table 12. Studies showing no relationship between rejection and method of MPA monitoring. Limited sampling strategies – Pre

(continued) 

Study Population Treatment Major 

Hesse45 2001 

Study design: Case series Length of followup: Mean 10.1 months 

Organ transplanted: Heart (Cardiac) Age: NR 

Dose: 1500 mg BID + dose reductions on clinical symptoms Concomitant medications: Tacrolimus Prednisone CsA 

There was nbetween preand graft hisbiopsy scorethey “do not correlation bconcentratioAR” 

Hubner56 2000 Study design: Case series Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 45y 

Dose: 1.0 g BID Concomitant medications: Cyclosporine A Methylprednisolone 

Did not obsepredose conbut no rejecduring MMF varying pred

Kiberd57 2004 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Mean 48 +/- 13y 

Dose: 2 g/day fixed Concomitant medications: Prednisone Neoral 

Day 3 MPA 

predicted la

Kuriata-Kordek54 2002 

Study design: Case control Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement group I: 38.12 +/- 9.5y, group II: 38.52 +/- 9.21y 

Dose: 2.0 g/day Concomitant medications: Cyclosporine Prednisone 

No significaobserved bewithout acutmonths pos

significant dbetween parejection du

Kuypers36 2004 

Study design: Case series Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Median 51.5y 

Dose: 0.5 g BID or 1 g BID Concomitant medications: Tacrolimus Methylprednisolone Daclizumab (31 patients) 

Same study 

Day 7 MPA 

p=0.90) was between paexperienced who did not
71

Table 12. Studies showing no relationship between rejection and method of MPA monitoring. Limited sampling strategies – Pre

(continued) 

Study Population Treatment Major 

Kuypers52 2003 

Study design: Prospective Cohort Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Mean 51.5y 

Dose: 1 g/day or 2 g/day Concomitant medications: Tacrolimus Methylprednisolone Daclizumab (31 patients) 

Same study 

Biopsy-provrelated to M

mg/L, rejectrespectivelyof MPA exprelated more MPA predosMPA AUC ifirst 6 weeks MMF group1g MMF grotransplant, tdeclined migroup’s AUC both groupsbaseline vasuggest thaconcentratiodrug monitoregarding ef

Kuypers15 2003 

Study design: Case series Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Mean 49.4 +/- 13.1y 

Dose: 1 g BID Concomitant medications: Methylprednisolone Tacrolimus Daclizumab 

Predose MP

were not sigpatients with or drug-relaauthors recorandomized examining tmore extensmeasuremecurve for MPmandatory t
72

Table 12. Studies showing no relationship between rejection and method of MPA monitoring. Limited sampling strategies – Pre

(continued) 

Study Population Treatment Major 

Kreis50 2000 Study design: RCT Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Range SIR: 43.5 +/- 10.9y (22-62y); CsA: 42.9 +/- 11.4 y (18-60y) 

Dose: 1 g BID Concomitant medications: Cyclosporine Corticosteroids Sirolimus 

There was nmean MPA between paacute rejectconcomitanp=0.50) or cp=0.39) groconcentratiosample size inference 

Mourad37 2000 

Study design: Case series Length of followup: 12 weeks 

Organ transplanted: Kidney (Renal) Age: Mean 46y Range 33-57y 

Dose: 1 g BID Concomitant medications: Cyclosporine Prednisolone 

Mean MPA were differeexperiencinmg/L, p<0.0significantly experiencinthose experevents or rep>0.05) 

Okamoto49 2005 Study design: Non randomized controlled trial Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 38 +/- 14y 

Dose: 25 mg/kg initially, then adjusted Concomitant medications: Cyclosporine n=35 Tacrolimus n=32 

MPA predossignificantly and without 

Orlando61 2006 Study design: Case series Length of followup: mean 31.5 + - 6.1 months 

Organ transplanted: Liver Age: Mean 60.1y Range 35-67y 

Dose: 250 mg per os BID increased weekly by 500 mg to dose of 1500 mg/day Concomitant medications: Cyclosporine Tacrolimus 

Mean MPA 

concentratiodifferent betrejectors (daform). Rejecat “therapeuMPA predosof 1.5 to 7.2 

Pillans59 2001 

Study design: Case series Length of followup: 1 month 

Organ transplanted: Kidney (Renal) Age: Range 21-65y 

Dose: 2 g/day Concomitant medications: Cyclosporine Prednisone 

No significaobserved in 

and without 
73

Table 12. Studies showing no relationship between rejection and method of MPA monitoring. Limited sampling strategies – Pre

(continued) 

Study Population Treatment Major 

Smak Gregoor60 2000 

Study design: Case series Length of followup: 1 year 

Organ transplanted: Kidney (Renal) Age: NR 

Dose: 1 g BID, 750 mg BID, 500 mg BID Concomitant medications: Prednisone 

No significaobserved bepredose (C0 

concentratioexperiencincompared wnot (2.3 vs. patients with concentratioexperience significant reand MPA prand 8 monthmonths (p=0significant cpredose conthese resultmonitoring oconcentratio

Tsaroucha24 2000 

Study design: Prospective Cohort Length of followup: liver-165d; small bowel-58d; kidney-373d; all post transplant 

Organ transplanted: Kidney (Renal) Liver Small bowel Age: Mean liver: 41.4 +/- 4.6y; small bowel: 18.7 +/- 3.9y; kidney: 44.3 +/- 2.7y 

Dose: liver: 0.0258 g/kg/day small bowel: 0.0822 g/kg/day kidney: 0.0194 g/kg/day Concomitant medications: Tacrolimus Steroids 

Mean MPA significantly patients who and those wmg/L, p=0.7

Wang51 1998 

Study design: RCT Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Range 35-59y 

Dose: 1. 1.0 g BID  2. 0.75 g BID Concomitant medications: Cyclosporine Corticosteroids Prednisone Methylprednisolone 

Very very wsignificant din mean Cm

patients in tBID groups. g BID group 0.75 g BID grejection epreported thadifferences between grodata were g
74

Table 12. Studies showing no relationship between rejection and method of MPA monitoring. Limited sampling strategies – Pre

(continued) 

Study Population Treatment Major 

Weber17 2001 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Range 2.2 - 17.8y 

Dose: 600 mg/m2 BSA BID up to 2 

g/day max Concomitant medications: Cyclosporine A Methylprednisolone 

MPA C0 did 

(p=0.07, resbetween rej

Yamani42 2000 

Study design: Retrospective Cohort Length of followup: 179 +/- 52 days 

Organ transplanted: Heart (Cardiac) Age: Mean 36 +/- 14y 

Dose: 2 g/day Concomitant medications: Cyclosporine Tacrolimus Prednisone 

There was nincidence of the patient sconcentratiowith those < p=0.92). Thdifference in concentratioand without transplant. W

concentratioincidence of lower at MPof > 2 mg/L mg/L (3.6 vswhen CSA o

were “subthsignificant drejection at concentratiomg/L (15.4 v
75

Table 13. Studies showing no relationship between rejection and method of MPA monitoring. Limited sampling strategies - 2h p

Study Population Treatment Major Findings/ 

Kuriata - Kordek54 2002 

Study design: Case control Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement group I: 38.12 +/- 9.5y, group II: 38.52 +/- 9.21y 

Dose: 2.0 g/day Concomitant medications: Cyclosporine Prednisone 

No significant difference was opatients with or without acute rpost-transplant in C2. No signif

observed between patients witrejection during the 1-year follo
76

Table 14. Studies showing no relationship between rejection and method of MPA monitoring. Limited sampling strategies - Othe

Study Population Treatment Major Findings/ 

Atcheson13 2004 

Study design: Prospective Cohort Length of followup: 1 month 

Organ transplanted: Kidney (Renal) Age: Mean 44.3 +/- 13.1y 

Dose: 1 g BID =10 

Concomitant medications: Cyclosporine n=32 Tacrolimus n=10 Simulect Diltiazem Prednisolone 

MPA AUC (as predicted by LSnot significantly different betwewithout biopsy-proven rejection p=0.25) 

Hale11 1998 

Study design: RCT Length of followup: 20 weeks 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement > 18 y Range: L: 47.8 +/- 11.5 y, I: 46.9 +/- 13.8y, H: 50.6 +/- 10.5y 

Dose: L: 0.45 g BID then adjusted I: 0.95 g BID then adjusted H: 1.7 g BID then adjusted Concomitant medications: Cyclosporine Corticosteroids 

Bivariate logistic regression berejection vs. MPA Cmax was no

Kuriata - Kordek54 2002 

Study design: Case control Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement group I: 38.12 +/- 9.5y, group II: 38.52 +/- 9.21y 

Dose: 2.0 g/day Concomitant medications: Cyclosporine Prednisone 

No significant difference was opatients with or without acute rpost-transplant in C60min or Cma

difference was observed betwewithout acute rejection during tC60min or Cmax

Kuypers36 2004 

Study design: Case series Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Mean 51.5y 

Dose: 0.5 g BID or 1 g BID Concomitant medications: Tacrolimus Methylprednisolone Daclizumab 

Same study as 52 (Prospective 

MPA Cmax (10.9 vs. 13 mg/L, p

significantly lower between patexperienced acute rejection an

Kuypers52 2003 

Study design: Prospective Cohort Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Mean 51.5y 

Dose: 1 g/day or 2 g/day Concomitant medications: Methylprednisolone Tacrolimus Daclizumab (31 patients) 

Same study as 36 (Case Series

MPA Cmax (10.95 vs. 13.0 mg/L

significantly different between biopsy-proven rejection 

Abbreviations: AUC=Area-under-the-concentration-time curve, Adj=adjust, BID=Twice Daily, BSA=Body Surface Area, C0=Predose Trough Serum o

Cmax=Maximum Serum or Plasma Concentration, H=High, I=Intermediate, L=Low, LSS=Limited Sampling Strategy, MMF=Mycophenolate Mofetil, M

RCT=Randomized Controlled Trial, y=Years
77

Table 14. Studies showing no relationship between rejection and method of MPA monitoring. Limited sampling strategies- Other 

Study Population Treatment Major Findings/ 

Mudge65 2004 Study design: RCT Length of followup: July 2002 - Feb 2003 

Organ transplanted: Kidney (Renal) Age: Mean 45.2 +/- 13.2y 

Dose: 1 g BID Concomitant medications: Cyclosporine Tacrolimus Prednisone 

MPA AUC (as predicted by LS

was not significantly lower in inand those without (30.7 vs. 34 

Wang51 1998 

Study design: RCT Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Range 35-59y 

Dose: 1. 1.0 g BID  2. 0.75 g BID Concomitant medications: Cyclosporine Corticosteroids Prednisone Methylprednisolone 

Very very weak supportive datdifferences were observed in m

for patients in the MMF 1 g BID One patient in the MMF 1 g BID group and no patients had an acute rejection epsiodereported that “There were no oMMF side effects between grodata were given 

Weber26 2002 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Mean 11.8y Range 3.2-16.0y 

Dose: 600 mg/m BID to a maximum of 2 g/day Concomitant medications: Cyclosporine A Methylprednisolone 

Cmax and AUC0-2 (i.e., C0, C75mi

as well (p=0.24 and p=0.06, rediscriminating between rejecto

Weber17 2001 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Range 2.2-17.8y 

Dose: 600 mg/m2 BSA BID up 

to 2 g/day max Concomitant medications: Cyclosporine Methylprednisolone 

Cmax did not perform as well (p

between rejectors and non-reje
78

Table 15. Studies showing some relationship between graft function or other efficacy parameter and method of MPA monitoring 

Method of 

Monitoring 

Study 

Author/Citation 

Population Treatment Major Findings/ 

Full AUC (AUC0-12) 

None - - - 

Limited sampling strategies – Predose (C0, Cmin, 

or C12) 

Cattaneo18 2001 Study design: Case series Length of followup: 9 months 

Organ transplanted: Kidney (Renal) Age: Mean AUC >40 μg.ml h: 31.9 +/- 9.0y, AUC <40 μg .ml h: 39 +/- 12.4y 

Dose: 2 g/day Concomitant medications: Cyclosporine Prednisone Neurol 

MPA C0 was significantly and p

creatinine clearance (r=0.5, p< 

Limited sampling strategies - 2h Post (C2) 

None - - - 

Limited sampling strategies - Other 

Cattaneo18 2001 

Study design: Case series Length of followup: 9 months 

Organ transplanted: Kidney (Renal) Age: Mean AUC >40 μg.ml h: 31.9 +/- 9.0y, AUC <40 μg.ml h: 39 +/- 12.4y 

Dose: 2 g/day Concomitant medications: Cyclosporine Prednisone Neurol 

MPA AUC (as predicted by C0, 

C120min) was significantly and p

creatinine clearance (r=0.52, p

Abbreviations: AUC=Area-under-the-concentration-time curve, C0=Predose Trough Serum or Plasma Concentration, Cmin=Minimum Serum or Plasma 

MPA=Mycophenolic Acid 
79

Table 16. Studies showing no relationship between graft function or other efficacy parameter and method of MPA monitoring 

Method of Monitoring Study Population Treatment Major Findings/ 

Full AUC (AUC0-12) 

Brunet106 2000 

Study design: Case control Length of followup: 38.5 months  (6-166 months) 

Organ transplanted: Kidney (Renal) Age: Mean 42.5 +/- 13.6y Range 18-65y 

Dose: 1 g, .075 g, and 0.5 g Concomitant medications: Prednisone CsA 

Although the authors report thapatients an inverse relationship concentrations and IMPDH actpatients with comparable MPA 

different degrees of IMPDH inhwide interindividual pharmacod

Limited sampling strategies – Predose (C0, Cmin, or C12) 

Brunet106 2000 

Study design: Case control Length of followup: 38.5 months  (6-166 months) 

Organ transplanted: Kidney (Renal) Age: Mean 42.5 +/- 13.6y Range 18-65y 

Dose: 1 g, .075 g, and 0.5 g Concomitant medications: Prednisone CsA 

Although the authors report thapatients an inverse relationship concentrations and IMPDH actpatients with comparable MPA exhibited different degrees of Isuggesting wide interindividuaactivity) 

Limited sampling strategies - 2h Post (C2) 

None - - - 

Limited sampling strategies- Other 

None - - - 

Abbreviations: AUC=Area-under-the-concentration-time curve, C0=Predose Trough Serum or Plasma Concentration, Cmin=Minimum Serum or Plasma 

CsA=Cyclosporin A, IMPDH=Inosine 5'-Monophosphate Dehydrogenase, MPA=Mycophenolic Acid, y=Years
80

Table 17. Studies showing some relationship between adverse events and method of MPA monitoring 

Study Population Treatment Major Findings/ 

Filler46 2000 

Study design: Case series Length of followup: 6.2 +/- 2.7 y (2.3-11.8) 

Organ transplanted: Kidney (Renal) Age: Mean 17.2 +/- 4.2 SD y 

Dose: 600 mg/m2 BID Concomitant medications: Cyclosporine Steroids 

Weak supportive data: Other thhigh MPA AUC0-12 (data not pro

abdominal pain and diarrhea, nadverse events 

Kuypers36 2004 

Study design: Case series Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Median 51.5y 

Dose: 0.5 g BID or 1 g BID Concomitant medications: Tacrolimus Methylprednisolone Daclizumab 

Same study as 52 (Prospective 

From 3 months on, patients wihad significantly higher MPA Awithout (p< 0.04). 

Note that a full AUC0-12 was ob

AUC at week 6, and a 4-h AUC (the 2- and 4-h AUCs were use

Mourad33 2001 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Range 32-68y 

Dose: 500 mg BID + adjustment for side effects Concomitant medications: Tacrolimus Corticosteroids 

Significant differences were ob36.04 mg·h/L, p=0.0006), and 

(0.16 vs. 0.12 (mg·h/L)/(mg/m2

(samples) with side effects and AUC cut off of 37.6 mg·h/L for 

sensitivity of 83.3% and a diag59.6%). ROC curves were not between these parameters 

Takahashi31 1995 

Study design: Non randomized controlled trial Length of followup: 12 weeks 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement ≥16y 1000 mg/day: Mean 37.7 +/- 6.3y 2000 mg/day: Mean 38.5 +/- 12.2y 3000 mg/day: Mean 41.0 +/- 10.3y 

Dose: 1000, 2000, or 3000 mg/d Concomitant medications: Cyclosporine Steroids (no description) 

Two patients (who had two of tvalues of > 90 mg/h/L) developAlthough other adverse events attempts were made to relate t

Abbreviations: AUC=Area-under-the-concentration-time curve, BID=Twice Daily, CMV=Cytomegalovirus, ROC= Receiver Operating Characteristic, 

SD=Standard Deviance, Y=years
81

Table 18. Studies showing some relationship between adverse events and method of MPA monitoring. Limited sampling strateg or C12) 

Study Population Treatment Major Findings/ 

Braun39 1998 

Study design: Prospective Cohort Length of followup: median 280 d (19-585) 

Organ transplanted: Kidney (Renal) Liver Age: Not reported 

Dose: 30-40 mg/kg/day Concomitant medications: Tacrolimus 

Weak supporting data: All 6 parejection had low MPA predose mg/L) and severe diarrhea. Twpatients had relatively high MPmg/L that “seemed to be assoinfection” (but no data were pro

Brusa41 2000 

Study design: Prospective Cohort Length of followup: >12 months 

Organ transplanted: Kidney (Renal) Age: Range 18 patients: 13-58y; 5 patients: 35-56y 

Dose: 250 to 1000 mg/day BID Concomitant medications: Cyclosporine Corticosteroids 

Very weak supporting data for monitoring: Of 7 patients with Mconcentrations > 4 μg/mL, 3 haevents (thrombocytopenia, leu

creatinemia) 

Borrows14 2006 

Study design: Case series Length of followup: 38 months median 25 months range 13-38 months 

Organ transplanted: Kidney (Renal) Age: Mean 46 +/- 9y Range 37 – 55y 

Dose: 750 mg – 2 g/day Concomitant medications: Tacrolimus Methylprednisolone Prednisone 

Median predose concentration 3.20 mg/L best discrimated bewithout anemia, leucopenia, diinfection, respectively 

Borrows69 2005 

Study design: Case series Length of followup: 30 months median 19 months range 6 – 30 months 

Organ transplanted: Kidney (Renal) Age: Mean 46 +/- 9y Range 37-55y 

Dose: 250-1500 mg/day corrected for body weight Concomitant medications: Tacrolimus Methylprednisolone Prednisone 

Infective diarrhea was associaconcentrations (p<0.001). MPA of MMF-related diarrhea were patients not experiencing diarrmg/L, p<0.001) 

Filler73 1998 

Study design: Case series Length of followup: range 49 to 503 days, mean 282 days 

Organ transplanted: Kidney (Renal) Age: Mean 15.8 +/- 1.6y Range 13 - 18 y 

Dose: 600 mg/m2 BID reduced to 320 mg/m2/day over 7 weeks Concomitant medications: Tacrolimus Methylprednisolone 

Except for one severe case of developed diarrhea at an MPA 5 mg/L. 

Abbreviations: AUC=Area-under-the-concentration-time curve, AZA=Azathioprine, BID=Twice Daily, C0=Predose Trough Serum or Plasma Concentr

or Plasma Concentration, CMV=Cytomegalovirus, CsA=Cyclosporin A, GI=Gastrointestinal, Hb=Haemoglobin, MMF=Mycophenolate Mofetil, MPA=

Not Reported, RCT=Randomized Controlled Trial, ROC= Receiver Operating Characteristic, RR=Relative Risk, TAC=Tacrolimus, y=Years
82

Table 19. Studies showing some relationship between adverse events and method of MPA monitoring. Limited sampling strateg

Study Population Treatment Major Findings/ 

No studies addressed this question - - - 
83

Table 20. Studies showing some relationship between adverse events and method of MPA monitoring. Limited sampling strateg

Study Population Treatment Major Findings/ 

Brunet66 2006 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Liver Age: Range 29 – 66y 

Dose: 1 g BID Concomitant medications: Tacrolimus Methylprednisolone Daclizumab 

No significant correlation was fevents and MPA C0, Cmax, or 

patients w/ GI adverse events and vomiting) had higher C40mi

these side effects (22.9 mg/L v

Mourad67 2001 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Mean 43y Range 16-67y 

Dose: 1 g BID Concomitant medications: Cyclosporine Anti-thymocyte globulin 

Of C0, C30min, and AUC, C30min 

discriminator between those weffects (32.99 vs. 7.45 mg/L, pspeculated that the high MPA C

g/day MMF dose) may explain adverse events in patients with “therapeutic range” and recomdose be divided into more than prevent early toxicity 

Mourad33 2001 

Study design: Case series Length of study design: 3 months 

Organ transplanted: Kidney (Renal) Age: Range 32-68y 

Dose: 500 mg BID + adjustment for side effects Concomitant medications: Tacrolimus Corticosteroids 

Significant differences were ob

vs. 7.66 mg/L, p=0.0091) and C

mg/L, p=-.0002) between patieeffects and those without. MPA C60min cut off of 8.09 mg/L 

diagnostic sensitivity of 77.8% specificity of 67.4%; ROC curvdifferent between C0, C60min, an

Mudge65 2004 Study design: RCT Length of followup: July 2002 - Feb 2003 

Organ transplanted: Kidney (Renal) Age: Mean 45.2 +/- 13.2y 

Dose: 1 g BID Concomitant medications: Cyclosporine Tacrolimus Prednisone 

Group w/toxicity: MPA AUC (a

C1, C3, and C6) = 39.3+-12.0 m

31.7+-7.9 mg/h/L p-value (gr. MPA AUC 

Pillans59 2001 

Study design: Case series Length of followup: 1 month 

Organ transplanted: Kidney (Renal) Age: Range 21-65y 

Dose: 2 g/day Concomitant medications: Cyclosporine Prednisone 

Patients with GI adverse eventlower MPA AUC (as predicted 

and C6) compared with patient

events (23.7 vs. 33.2 mg.h/L, pfinding may suggest poor absolocal GI effects. (Three of the 4 events also experienced acute 

Abbreviations: AUC=Area-under-the-concentration-time curve, BID=Twice Daily, C0=Predose Trough Serum or Plasma Concentration, GI=Gastrointe

Sampling Strategy, MMF=Mycophenolate Mofetil, MPA=Mycophenolic Acid, RCT=Randomized Controlled Trial, ROC= Receiver Operating Charact
84

Table 21. Studies showing no relationship between adverse events and method of MPA monitoring 

Study Population Treatment Major Findings/ 

Brunet66 2006 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Liver Age: Range 29 – 66y 

Dose: 1 g twice a day Concomitant medications: Tacrolimus Methylprednisolone Daclizumab 

No significant correlation was fevents and AUC 

Hale11 1998 

Study design: RCT Length of followup: 20 weeks 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement > 18 y Range: L: 47.8 +/- 11.5 y, I: 46.9 +/- 13.8y, H: 50.6 +/- 10.5y 

Dose: L: 0.45 g BID then adjusted I: 0.95 g BID then adjusted H: 1.7 g BID then adjusted Concomitant medications: Cyclosporine Corticosteroids 

P value between each specifie(diarrhea, nausea, leucopenia, infection and abdominal pain) vsignificant (p>0.05). However, the risk of premature study witevents were both significantly dose 

Kuypers36 2004 

Study design: Case series Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Median 51.5y 

Dose: 0.5 g BID or 1 g BID Concomitant medications: Tacrolimus Methylprednisolone Daclizumab 

Same study as 52 (Prospective 

MPA AUC was not significantly and without infection. MPA AUsignificantly higher in patients wwith those without 

Kuypers52 2003 

Study design: Prospective Cohort Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Median 51.5y 

Dose: 1 g/day or 2 g/day Concomitant medications: Methylprednisolone Tacrolimus Daclizumab (32 patients) 

same study as 36 (Case series) 

Diarrhea was not significantly r

Lu29 2005 

Study design: Non randomized Clinical Trial Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 40.0 +/- 12.0y 

Dose: mean 58.0 +/- 10.0 kg Concomitant medications: Cyclosporine Prednisone Tacrolimus 

There was no significant differebetween patients with MPA AU

μg·h/mL. 

Abbreviations: AUC=Area-under-the-concentration-time curve, AZA=Azathioprine, BID=Twice Daily, C0=Predose Trough Serum or Plasma ConcentrSerum or Plasma Concentration, CMV=Cytomegalovirus, ECMPS=Enteric-Coated Mycophenolate Sodium, GI=Gastrointestinal, H=High, I=Intermedi

Sampling Strategy, MF=Mycophenolate Mofetil, MPA=Mycophenolic Acid, NR=Not Reported, RCT=Randomized Controlled Trial, y=Years
85

Table 21. Studies showing no relationship between adverse events and method of MPA monitoring (continued) 

Study Population Treatment Major Findings/ 

Mourad67 2001 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Mean 43y Range 16-67y 

Dose: 1 g BID Concomitant medications: Cyclosporine Anti-thymocyte globulin 

Mean MPA AUC was significanexperienced adverse events couneventful outcomes (52.1 vs. 

AUC was not a significant discwith and without side effects 

Mourad37 2000 

Study design: Case series Length of followup: 12 weeks 

Organ transplanted: Kidney (Renal) Age: Mean 46y Range 33-57y 

Dose: 1 g BID Concomitant medications: Cyclosporine Prednisolone 

Mean MPA predose concentradifferent for those experiencing mg/L, p>0.05) compared to thorejection nor adverse events. Msimilar with 15.5, 72.7, and 42.

rejection, MMF toxicity, and neevents, respectively (p value n

Satoh35 2005 

Study design: Prospective Cohort Length of followup: 28 days 

Organ transplanted: Kidney (Renal) Age: Mean AZA: 37.9 +/- 11.5y MMF: 44.3 +/- 11.6y 

Dose: 1.0 – 2 g/day Concomitant medications: Tacrolimus Methylprednisolone Prednisone 

MPA AUC was not significantly viral infections compared to thoμg·h/mL, respectively) 

Sumethkul32 2005 

Study design: Case series Length of followup: 3-8 months 

Organ transplanted: Kidney (Renal) Age: Mean 39 +/- 9y 

Dose: 720 mg BID Concomitant medications: Cyclosporine Prednisone 

Only very weak inferential evidwas to assess delivery of MPA correlate MPA measurements patients with a AUC0-12 for MPA 

less diarrhea and 1 patient needosage 
86

Table 21. Studies showing no relationship between adverse events and method of MPA monitoring (continued) 

Study Population Treatment Major Findings/ 

van Gelder12 1999 

Study design: RCT Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Range L: 47.8 +/- 11.5y; I: 46.9 +/- 13.8y; H: 50.6 +/- 10.5y 

Dose: L: 16.1 ug hr/ml I: 32.2 ug hr/ml H: 60.6 ug hr/ml Concomitant medications: Cyclosporine Prednisone Corticosteroids 

The relation between prematuradverse events and median ln statistically significant (p=0.434showed that only the prematur(and not other) adverse events to MMF dose. This suggests thsystemic, drug concentrations, the GI adverse events. The ausignificance is lost when only tconcentrations are used in the analysis and thus caution agaiadjustments on a limited numbconcentrations. Note that the ffull 12h AUCs whereas the lateAUC0-12 (as predicted by LSS o

C75min,2h) 

Weber26 2002 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Mean 11.8y Range 3.2 - 16.0y 

Dose: 600 mg/m2 BID to a 

maximum of 2 g/day Concomitant medications: Cyclosporine A Methylprednisolone 

There was no significant associncidence of adverse events (lediarrhea, anemia, or thromboc

Weber17 2002 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Range 2.2 - 17.8y 

Dose: 600 mg/m2 BID up to 2 

g/day max Concomitant medications: Cyclosporine A Methylprednisolone 

There was no significant associncidence of adverse events (lediarrhea, vomiting, or abdominMPA Cmax and free MPA AUC 

between patients with or witholeukemia] 
87

Table 22. Studies showing no relationship between adverse events and method of MPA monitoring. Limited sampling strategies 

C12) 

Study Population Treatment Major Findings/ 

Behrend25 1997 Study design: RCT Length of followup: at least 1 year 

Organ transplanted: Kidney (Renal) Age: Not reported 

Dose: 2 g/day or 3 g/day; dose per body weight was 22 to 54 mg/Kg; mean 83 mg/kg + - 8.4 body weight Concomitant medications: Cyclosporine Corticosteroids 

Very very weak supportive dat“there is no clearcut relationshconcentrations and rejection, ainfections” but provide no datainterindividual variability in MP

predose) concentrations is “by correlation to ...dose...” but do 

Bilbao62 2006 Study design: Case series Length of followup: mean 39 + - 20 months; range 3 to 72 months. 

Organ transplanted: Liver Age:Mean 59 +/- 6y 

Dose: Initial dose of 500 mg/12h; reaching dose of 1 g each 12h for 2 weeks. Concomitant medications: Cyclosporine (neoral) Tacrolimus 

Although adverse events (leukreported, no attempts were maMPA predose (or C0 or predos

adjustments were based on toevents and not on predose conthey “tried to avoid concentrati

Borrows14 2006 

Study design: Case series Length of followup: minimum of 12 months median 25 months range 13-38 months 

Organ transplanted: Kidney (Renal) Age: Mean 46 +/- 9y Range 37–55y 

Dose: 750 mg – 2 g/day Concomitant medications: Tacrolimus Methylprednisolone Prednisone Corticosteroids Ganciclovir (3 months) Co-Trimoxazole (6 months) Isoniazid and pyridoxine (IndoAsians and those with previous TB) Basilizimab or Daclizumab (79 patients) 

No association was seen betwand platelet count. No associaMPA concentration and the deinfection 

Abbreviations: AUC=Area-under-the-concentration-time curve, BID=Twice Daily, BSA=Body Surface Area, C0=Predose Trough Serum or Plasma Co

Serum or Plasma Concentration, CMV=Cytomegalovirus, MMF=Mycophenolate Mofetil, MPA=Mycophenolic Acid, MPAG=Mycophenolic Acid GluPSL=Predonisolone, RCT=Randomized Controlled Trial, TB=Tuberculosis, y=Years
88

Table 22. Studies showing no relationship between adverse events and method of MPA monitoring. Limited sampling strategies 

C12) (continued) 

Study Population Treatment Major Findings

Brunet66 2006 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Liver Age: Range 29–66y 

Dose: 1 g twice a day Concomitant medications: Tacrolimus Methylprednisolone Daclizumab 

No significant correlation was fevents and MPA C0

Cattaneo18 2001 Study design: Case series Length of followup: 9months 

Organ transplanted: Kidney (Renal) Age: Mean AUC>40 ug·ml h: 

31.9 +/- 9.0y AUC<40 ug·ml 

h: 39 +/- 12.4y; Range 19-61y 

Dose: 2 g/day Concomitant medications: Cyclosporine Prednisone CSA Neoral 

Total MPA predose concentratsignificantly with red blood cell free MPA fraction correlated nesignificantly) 

Deierhoi75 1993 

Study design: RCT Length of followup: phase I trial: mean 26 months range 22 - 28 months rescue: mean 20 months range 16 - 24 months 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement phase I: older than 18y, rescue: older than 16y 

Dose: phase I: 1500 - 3000 mg/day rescue: 2000 mg/day and 3000-3500 mg/day if no response in first week to 2000 mg Concomitant medications: Phase I: Minnesota antilymphocyte globulin(MALG) Prednisone Methylprednisolone Cyclosporine Rescue: Corticosteroids Cyclosporine 

Authors stated that “there was between serum concentrations the occurrence of side effects obut no data were given 

Hale11 1998 

Study design: RCT Length of followup: 20 weeks 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement > 18y Range: L: 47.8 +/- 11.5 y, I: 46.9 +/- 13.8y, H: 50.6 +/- 10.5y 

Dose: L: 0.45 g BID then adjusted I: 0.95 g BID then adjusted H: 1.7g BID then adjusted Concomitant medications: Cyclosporine Corticosteroids 

P values between each specifi(diarrhea, nausea, CMV, urinaabdominal pain) vs. MPA C0 w

(p>0.05) 
89

Table 22. Studies showing no relationship between adverse events and method of MPA monitoring. Limited sampling strategies 

C12) (continued) 

Study Population Treatment Major Findings

Kuriata - Kordek54 2002 

Study design: Case control Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement group I: 38.12 +/- 9.5y, group II: 38.52 +/- 9.21y 

Dose: 2.0 g/day Concomitant medications: Cyclosporine Prednisone 

No significant difference was opatients with or without leucopfollowup in C0

Okamoto49 2005 Study design: Non randomized controlled trial Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 38 +/- 14 y 

Dose: 25 mg/kg initially, then adjusted afterwards Concomitant medications: Cyclosporine n=35 Tacrolimusn=32 

MPA predose concentration wadifferent in patients with and w

Kiberd57 2004 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age:Mean 48 +/- 13y 

Dose: 2 g/day fixed Concomitant medications: Prednisone Neoral 

MPA C0, did not significantly p

Krumme47 1998 Study design: Case series Length of followup: 2 months 

Organ transplanted: Kidney (Renal) Age: Range 46 +/-11y 

Dose: 1 g BID Concomitant medications: Cyclosporine Methylprednisolone 

Incidences of CMV infection anwere not significantly different without rejection, but no data wrelation between MPA predose adverse events 

Kuypers36 2004 

Study design: Case series Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Mean median 51.5y 

Dose: 0.5 g BID or 1 g BID Concomitant medications: Tacrolimus Methylprednisolone Daclizumab 

Same study as 52 (Prospective 

MPA C0 was not significantly h

diarrhea compared with those 

Kuypers15 2003 

Study design: Case series Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Mean 49.4 +/- 13.1y 

Dose: 1 g BID Concomitant medications: Methylprednisolone Tacrolimus Daclizumab 

Predose MPA concentrations (

different in patients with or withevents. The authors recommenrandomized comparative trial eof frequent, more extensive phmeasurements like area under its metabolites, is mandatory to the necessity for routine therapmycophenolate mofetil in rena
90

Table 22. Studies showing no relationship between adverse events and method of MPA monitoring. Limited sampling strategies 

C12) (continued) 

Study Population Treatment Major Findings

Kuypers52 2003 

Study design: Prospective Cohort Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Mean 51.5y 

Dose: 1 g/day or 2 g/day Concomitant medications: Methylprednisolone Tacrolimus Daclizumab (31 patients) 

Same study as 36 (Case series

Diarrhea was not significantly r

time course of MPA exposure 

more to MMF dose than to MPconcentrations. That is, MPA A

~40% in the first 6 weeks post-MMF group, but by only 17% in 3 months post-transplant, the 2

declined minimally whereas the 

decreased to its nadir. In both 

returned to baseline values. Ththat using MPA predose concetherapeutic drug monitoring maregarding efficacy or toxicity 

Merkel22 2005 Study design: Retrospective Cohort Length of followup: 16 months, mean 5.7 months 

Organ transplanted: Kidney (Renal) Age: Mean 44 +/- 13.6y Range 13–63y 

Dose: 0.5 - 1.0 g BID Concomitant medications: Cyclosporine Prednisone Corticosteroids 

There was no correlation betwconcentrations and MPA predovalue not provided) 

Mourad67 2001 

Study design:v Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Mean 43y Range 16-67y 

Dose: 1 g BID Concomitant medications: Cyclosporine Anti-thymocyte globulin Steroids 

There was no significant differeMPA C0 (predose or trough) be

adverse events and those with

significant discriminator betweeside effects 

Mourad37 2000 

Study design: Case series Length of followup: 12 weeks 

Organ transplanted: Kidney (Renal) Age: Mean 46y Range 33-57y 

Dose: 1g BID Concomitant medications: Cyclosporine Prednisolone 

Mean MPA predose concentrasignificantly different for those toxicity (3.1 vs. 2.2 mg/L, p>0.0experiencing neither rejection AUC data were similar with 15

associated with rejection, MMF rejection nor adverse events, rprovided) 
91

Table 22. Studies showing no relationship between adverse events and method of MPA monitoring. Limited sampling strategies 

C12) (continued) 

Study Population Treatment Major Findings

Pawinski64 2006 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Range 17–62y 

Dose: 0.5 - 2 g/day Concomitant medications: Cyclosporine Tacrolimus Prednisone 

No correlation was found betwwbc count or hematocrit values 

Shaw20 2000 Study design: Prospective Cohort Length of followup: 90 days 

Organ transplanted: Kidney (Renal) Age: Range 47 +/-9.7y 

Dose: 1 g BID Concomitant medications:  Neoral Steriods 

Weak supportive data: The autoccurrence of diarrhea was noconcentrations of either total opredose, or MPAG predose vaspecific data 

Sugioka76 2006 

Study design: Case series Length of followup: 28 days 

Organ transplanted: Kidney (Renal) Age: Range MPA group: 7 - 69y, PSL group: 11 - 66y 

Dose: MPA group: 250 or 1750 mg/day Concomitant medications: Cyclosporine Tacrolimus 

No significant differences were concentration between patients adverse events of or diarrhea 

van Besouw72 1999 

Study design: Case series Length of followup: 8 months 

Organ transplanted: Kidney (Renal) Age: Not reported 

Dose: 2 g/day – 1 g/day Concomitant medications: Prednisone 

MPA predose concentration waleukocyte counts (Spearman r= 

van Gelder12 1999 

Study design: RCT Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Range L: 47.8 +/- 11.5y; I: 46.9 +/- 13.8y; H: 50.6 +/- 10.5y 

Dose: L: 16.1 ug hr/ml I: 32.2 ug hr/ml H: 60.6 ug hr/ml Concomitant medications: Cyclosporine Prednisone Corticosteroids 

The relation between prematurto adverse events and median 

significant (p=0.512) 

Weber26 2002 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Mean 11.8y Range 3.2 - 16.0y 

Dose: 600 mg/m2 twice a day to 

a maximum of 2 g/day Concomitant medications: Cyclosporine A Methylprednisolone 

There was no significant assoc

incidence of adverse events (lediarrhea, anemia, or thromboc
92

Table 22. Studies showing no relationship between adverse events and method of MPA monitoring. Limited sampling strategies 

C12) (continued) 

Study Population Treatment Major Findings

Weber17 2001 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Range 2.2 - 17.8y 

Dose: 600 mg/m2 BSA twice a 

day up to 2 g/day max Concomitant medications: Cyclosporine A Methylprednisolone 

There was no significant assoc

incidence of adverse events (lediarrhea, vomiting, or abdomin

Yamani42 2000 

Study design: Retrospective Cohort Length of followup: 179 +/- 52 days 

Organ transplanted: Heart (Cardiac) Age: Mean 36 +/- 14y 

Dose: 2 g/day Concomitant medications: Cyclosporine Tacrolimus Prednisone 

There was no significant differeblood cell count, total lymphoclymphocytes in MPA predose c2, 2-5, and > 4 mg/L) 
93

Table 23. Studies showing no relationship between adverse events and method of MPA monitoring. Limited sampling strategies 

Study Population Treatment Major Findings/ Co

Kiberd57 2004 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Mean 48 +/- 13y 

Dose: 2 g/day fixed Concomitant medications: Prednisone Neoral 

MPA C2 did not significantly predict t

Kuriata - Kordek54 2002 

Study design: Case control Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement group I: 38.12 +/- 9.5y, group II: 38.52 +/- 9.21y 

Dose: 2.0 g/day Concomitant medications: Cyclosporine Prednisone 

No significant difference was observeor without during the 1-year followup 

Abbreviations: MPA=Mycophenolic Acid, y=Years
94

Table 24. Studies showing no relationship between adverse events and method of MPA monitoring. Limited sampling strategies 

Study Population Treatment Major Findings/ Com

Atcheson13 2004 

Study design: Prospective Cohort Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 44.3 +/- 13.1 y 

Dose: 1 g BID Concomitant medications: Cyclosporine n=32 Tacrolimus n=10 Simulect Diltiazem Prednisolone 

Patients who experienced one or more events (thrombocytopenia, leucopeniahave significantly higher MPA AUC0-6 (values compared to patients without th(p=0.18). The latter may suggest that Mmay be related to local drug concentraMPA AUC was a better predictor of headverse events compared with total M

Brunet66 2006 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Liver Age: Range 29 – 66y 

Dose: 1 g BID Concomitant medications: Tacrolimus Methylprednisolone Daclizumab 

No significant correlation was found beand MPA Cmax except for patients w/ G

(diarrhea and/or nausea and vomiting) 

Deierhoi75 1993 

Study design: RCT Length of followup: phase I trial: mean 26 months range 22 - 28 months rescue: mean 20 months range 16 - 24 months 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement phase I: older than 18y, rescue: older than 16y 

Dose: phase I: 1500 - 3000 mg/day rescue: 2000 mg/day and 3000-3500 mg/day if no response in first week to 2000 mg Concomitant medications: Phase I: Minnesota antilymphocyte globulin(MALG) Prednisone Methylprednisolone Cyclosporine Rescue: Corticosteroids Cyclosporine 

Authors stated that “there was no cleaserum levels [Cmax and trough] and the 

effects or rejection episodes”, but no d

Abbreviations: AUC=Area-under-the-concentration-time curve, BID=Twice Daily, BSA=Body Surface Area, C0=Predose Trough Serum or Plasma Co

Serum or Plasma Concentration, CMV=Cytomegalovirus, GI=Gastrointestinal, LSS=Limited Sampling Strategy, LSS=Limited Sampling Strategy, MPAMPAG=Mycophenolic Acid Glucuronide, MPA=Mycophenolic Acid, NR= Not Reported, PSL=Prednisolone, RCT=Randomized Controlled Trial, WBy=Years
95

Table 24. Studies showing no relationship between adverse events and method of MPA monitoring. Limited sampling strategies – Other (

Study Population Treatment Major 

Hale11 1998 

Study design: RCT Length of followup: 20 weeks 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement > 18 y Range: L: 47.8 +/- 11.5 y, I: 46.9 +/- 13.8y, H: 50.6 +/- 10.5y 

Dose: L: 0.45 g BID then adjusted I: 0.95 g BID then adjusted H: 1.7 g BID then adjusted Concomitant medications: Cyclosporine Corticosteroids 

P values beadverse eveCMV, urinarabdominal psignificant (

Heller77 2007 

Study design: Prospective cohort Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Mean 53.4y 

Dose: Fixed dose group: 1 g BID, Concentration-controlled group: target concentration of 30-60 mg*h/L Concomitant medications: Cyclosporine Tacrolimus 

MPA AUC, 

C0.5, and C2

different betsuffered an versus thos

Kaplan21 1999 

Study design: Case series Length of followup: >2 weeks 

Organ transplanted: Kidney (Renal) Age: Range chronic renal subjects 46.7 +/- 9.2y; renal patients without chronic insufficiency 43.3 +/- 8/6y 

Dose: 1.75 +/- 0.3 g/day Concomitant medications: Not reported 

No p values not appear tMMF dose abetween MPevents. MPA LSS of C0, C

C120min. [Leu

patients, 3 ofree MPA A1.92 μg.h/mfifth highest μg.h/mL); a 

free MPA Aexperience and CMV ocand thus cofree MPA A

Kiberd57 2004 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Mean 48 +/- 1 3y 

Dose: 2 g/day fixed Concomitant medications: Prednisone Neoral 

MPA AUC, 

C1, C2, and 

predict toxic
96

Table 24. Studies showing no relationship between adverse events and method of MPA monitoring. Limited sampling strategies – Other (

Study Population Treatment Major 

Kuriata-Kordek54 2002 

Study design: Case control Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Inclusion requirement group I: 38.12 +/- 9.5y, group II: 38.52 +/- 9.21y 

Dose: 2.0g/day Concomitant medications: Cyclosporine Prednisone 

No significaobserved bewithout durC40min, C60m

Kuypers36 2004 

Study design: Case series Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Median 51.5y 

Dose: 0.5 g BID or 1 g BID Concomitant medications: Tacrolimus Methylprednisolone Daclizumab 

Same study 

(Prospective MPA Cmax win patients wwith those w

Kuypers52 2003 

Study design: Prospective Cohort Length of followup: 12 months 

Organ transplanted: Kidney (Renal) Age: Mean 51.5y 

Dose: 1 g/day or 2 g/day Concomitant medications: Methylprednisolone Tacrolimus Davlizumab (31 patients) 

Same study 

series) Diarrhea warelated to M

Le Meur10 2007-10-30 

Study design: RCT Length of followup: 12 months 

Organ transplanted: Kidney Age: Fixed dose group 49 +/- 13y Concentration-controlled group: 50 +/- 14y 

Fixed dose group: 1 g BID; Concentration-controlled group: Days 1-7, 1 g BID, then dose to target AUC of 40 mg*h/L Concomitant medications: Cyclosporine Methylprednisolone Basiliximab Trimethoprimsulfamethoxazole 

There was n(p>0.05) in events (totaanemia, leuinfections, cinfections, binfections) bcontrolled aexcept for hoccurred moconcentratioevent, p<0.0of patients icontrolled arespectivelyadverse eve

Okamoto49 2005 Study design: Non randomized controlled trial Length of followup: NR 

Organ transplanted: Kidney (Renal) Age: Mean 38 +/- 14 years 

Dose: 25 mg/kg initially, then adjusted afterwards Concomitant medications: Cyclosporine n=35 Tacrolimus n=32 

MPA AUC0-

different in padverse effe
97

Table 24. Studies showing no relationship between adverse events and method of MPA monitoring. Limited sampling strategies – Other (

Study Population Treatment Major 

Pawinski64 2006 

Study design: Case series Length of followup: 3 months 

Organ transplanted: Kidney (Renal) Age: Range 17–62y 

Dose: 0.5 - 2 g/day Concomitant medications: Cyclosporine Tacrolimus Prednisone 

No correlatiMPA AUC (

C0.5, and C2

hematocrit v

Shaw20 2000 Study design: Prospective Cohort Length of followup: 90 days 

Organ transplanted: Kidney (Renal) Age: Range 47 +/-9.7y 

Dose: 1 g BID Concomitant medications: Neoral Steriods 

Weak suppostated “The was not assconcentratioMPA AUC, predose valspecific data21% higher AUC in patiecompared wMPA AUC wC0, C20min, C

Sugioka76 2006 

Study design: Case series Length of followup: 28 days 

Organ transplanted: Kidney (Renal) Age: Range MPA group: 7-69y,  PSL group: 11-66y 

Dose: MPA group: 250 or 1750 mg/day Concomitant medications: Cyclosporine A Tacrolimus Prednisone 

No significaobserved in 

C3, C4, C6, a

patients with events of le

Weber26 2002 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Mean 11.8y Range 3.2-6.0y 

Dose: 600 mg/m2 BID to a maximum 

of 2 g/day Concomitant medications: Cyclosporine A Methylprednisolone 

There was nbetween Cmand C4), or 

C40min, C75m

incidence of (leucopeniaanemia, or t
98

Table 24. Studies showing no relationship between adverse events and method of MPA monitoring. Limited sampling strategies – Other (

Study Population Treatment Major 

Weber17 2001 

Study design: Case series Length of followup: 6 months 

Organ transplanted: Kidney (Renal) Age: Range 2.2-17.8y 

Dose: 600 mg/m2 BID up to 2 g/day 

maximum Concomitant medications: Cyclosporine A Methylprednisolone 

There was nbetween Cm

and C4), or 

C40min, C75mincidence of (leucopeniavomiting, or that free MP

AUC0-12 wer

between painfections a
99

Table 25. Influence of age on the utility of monitoring mycophenolic acid in patients who receive a solid organ transplant 

Study Organ n Age % Male Race Medications Health Outcomes Reported 

Borrows69

2005 

Kidney (Renal) 

117 Mean: 

46 +/- 9y Range: 37-55y 

58.1 White 55.6% 

Indo-Asian 23.1% Afro-Carib 17.9% Other 3.4% 

Tacrolimus Methylprednisolone Prednisone 

Infective diarrhea, patient survival, graft survival, biopsy proven acute rejection 

No associaMPA predo

Bunchman23

2001 

Kidney (Renal) 

100 Inclusion 

requirement 3 months - 18 years 

68 64 patients 

were from North America, 4 from Australia and 32 from Europe 

600 mg/m2 BID up 

to 1 g BID 

Presumptive rejection, diarrhea, anemia, sepsis, leukopenia, renal function (creatinine clearances) % rejections and adverse events by age group and AUC and Cmax Age groups: <6y 6 to 12y 12 to 18y < 2y 

No associabetween loplasma conincidence oadverse ev

Cattaneo182001 

Kidney (Renal) 

46 Range 

19-61y 

63 NR 2 g/day Creatinine 

clearance, renal function, rejection episodes, serum creatinine concentration, creatinine clearance 

Patients wi

μg/mL.h grsignificantly the < 40 μg

Dipchand55

2001 

Heart (Cardiac) 

44 Range 

29 d-23.5y Median 6.3y 

61 NR various: 15-159 

mg/kg 

Rejection Increased 

concentratiassociated 

Abbreviations: AUC=Area-under-the-concentration-time curve, BID=Twice daily, Cmax=Maximum Serum or Plasma Concentration, MPA=Mycopheno

MPAG=Mycophenolic Acid Glucuronide, MMF=Mycophenolate Mofetil, NR=Not Reported, PK=Pharmacokinetic, y=Years 
100

Table 25. Influence of age on the utility of monitoring mycophenolic acid in patients who receive a solid organ transplant (contin

Study Organ n Age % Male Race Medications Health Outcomes Reported 

Wang 122

2007 

Kidney (Renal) 

48 Elderly 

group: 65.6 +/- 3.6y Adult group: 39.6 +/- 14.3y 

67 Chinese Cyclosporine 

MMF Prednisone 

Acute rejection Severe adverse events: Pneumonia, leukopenia, death 

MPA AUC the elderly younger adwas no sigpredose, ppeak timeselderly patievents was that of eldesevere adv

Weber17

2001 

Kidney (Renal) 

24 Range: 

2.2 - 17.8y 

61.1 All patients 

were white 

Cyclosporine Methylprednisolone 

Acute rejection, adverse events (leucopenia, infections) 

In the first wnot at later low MPA A

associated MPA AUC0

concentratiassociated rejection 

Weber, L112

1998 

Kidney (Renal) 

28 Children 

Mean 10.7 +/ - 0.72y Range 5.9 - 15.3y Adults Mean 45.9 +/- 4.1y Range 20.1 - 59.2y 

64 NR Children: 600 

mg/m2 body 

surface area BID Adults: 1 g BID 

Transplant dysfunction all subjects 

Mean MPA 

patients onwas 40% hcomparable The AUC0-one and thbetween chChildren ditime profileafter oral amg/m2 bod

that, in genthe profiles mg MMF tw
101

Table 26. Influence of gender on the utility of monitoring mycophenolic acid in patients who receive a solid organ transplant 

Study Organ n Age % Male Race Medications Health Outcomes Reported 

Borrows 69

2005 

Kidney (Renal) 

117 Mean: 

46 +/- 9y Range: 37-55y 

58.1 White 55.6% 

Indo-Asian 23.1 AfroCarib 17.9% Other 3.4% 

Tacrolimus Methylprednisolone Prednisone 

Infective diarrhea, patient survival, graft survival, biopsy proven acute rejection 

Multishowwas predcompsize: 1.31

Kuypers5 2

2003 

Kidney (Renal) 

100 Meidan: 

51.5y 

59 NR Daclizumab (31 

patients) Tacrolimus Methylprednisolone 

Delayed graft function, mild hepatic dysfunction (abnormal liver function) 

MPA not ingend

Lu29

2005 

Kidney (Renal) 

29 Mean: 

40.0 +/- 12.0y 

58.6 NR Cyclosporine 

Prednisone Tacrolimus 

Rejection MPA 

highe34.3MMF 

Abbreviatons: AUC=Area-under-the-concentration-time curve, MMF=Mycophenolate Mofetil, MPA=Mycophenolic Acid, NR=Not Reported, PK=Pha
102

Table 27. Influence of ethnicity on the utility of monitoring mycophenolic acid in patients who receive a solid organ transplant 

Study Organ n Age % Male Race Medications Health Outcomes Reported 

Borrows 69

2005 

Kidney (Renal) 

117 Mean : 

46 +/- 9y Range: 37-55y 

58.1 White 55.6% 

Indo-Asian 23.1 Afro-Carib 17.9% Other 3.4% 

Tacrolimus Methylprednisolone Prednisone 

Infective diarrhea, patient survival, graft survival, biopsy proven acute rejection 

No associa(White, Indother) and concentrati

Shaw202000 

Kidney (Renal) 

33 Range: 

47+/-9.7y 

70 African 

American: 13 Caucasian: 20 

Neoral Steriods Impaired Renal 

Function 

No significaAUC valueconcentratistudy periocompared 

Abbreviations: AUC=Area-under-the-concentration-time curve, MPA=Mycophenolic Acid, y=Years
103

Table 28. Influence of the concomitant use of calcineurin inhibitors on the utility of monitoring mycophenolic acid in patients wh

transplant 

Study Organ n Age % Male Race Medications Health Outcomes Reported 

Atcheson13

2004 

Kidney (Renal) 

42 Mean: 

44.3 +/- 13.1y 

57 Caucasian 

98% 

Cyclosporine n=32 Tacrolimus n=10 Simulect Diltiazem Prednisolone 

Rejection, gastrointestinal events, anemia, hematological events thrombocytopenia and leukopenia), infectious events 

Borrows69

2005 

Kidney (Renal) 

117 Mean: 

46 +/- 9y Range: 37-55y 

58.1 White 

55.6% Indo-Asian 23.1% Afro-Carib 17.9% Other 3.4% 

Tacrolimus Methylprednisolone Prednisone 

Infective diarrhea, patient survival, graft survival, biopsy proven acute rejection 

Cantin58

2002 

Heart (Cardiac) 

26 Mean: 54.4 +/- 

14y Range: 22–72y 

73 NR Cyclosporine 

Tacrolimus Corticosteroids 

Overall rejection 

Abbreviations: AE=Adverse events, AUC=Area-under-the-concentration-time curve, CMV=Cytomegalovirus, CNI=Calcineurin Inhibitors, CsA=CycloCyA=Cyclosporine, GI=Gastrointestinal, MPA=Mycophenolic Acid, NR=Not Reported, PSL-Prednisolone, TAC=Tacrolimus, y=Years
104

Table 28. Influence of the concomitant use of calcineurin inhibitors on the utility of monitoring mycophenolic acid in patients w

transplant (continued) 

Study Organ n Age % Male Race Medications Health Outcom

Reported 

Heller77

2007 

Kidney (Renal) 

290 Mean: 

52.5 +/- 13.4y 

62 White 

89.8% Black 1.9% Asian 3.2% Other 5.2% 

Cyclosporine n=110 Tacrolimus n=180 

Diarrhea 

Hesse45

2001 

Heart (Cardiac) 

20 NR NR NR Tacrolimus 

Prednisone CsA 

Acute rejection (biopscore comparison) 
105

Table 28. Influence of the concomitant use of calcineurin inhibitors on the utility of monitoring mycophenolic acid in patients w

transplant (continued) 

Study Organ n Age % Male Race Medications Health Outcom

Reported 

Kuypers36

2004 

Kidney (Renal) 

100 Median 51.5y 59 NR Tacrolimus 

Methylprednisolone Daclizumab 

Acute rejection 

Lu29

2005 

Kidney (Renal) 

29 Mean: 

40.0 +/- 12.0y 

58.6 NR Cyclosporine 

Prednisone Tacrolimus 

Acute rejection 
106

Table 28. Influence of the concomitant use of calcineurin inhibitors on the utility of monitoring mycophenolic acid in patients w

transplant (continued) 

Study Organ n Age % Male Race Medications Health Outcom

Reported 

Mandla382006 

Kidney (Renal) 

78 CsA: 68 Tac: 10 

Mean: 54y Range: 19-77y 

73.1 NR Tacrolimus 

Methylprednisolone Prednisone Cyclosporine 

Acute rejection,hypoalbumdelayed graft functio

Mourad33

2001 

Kidney (Renal) 

51 Range: 

32-68y Median: 49y 

57 NR Tacrolimus 

Corticosteroids 

Side effects 

Naito108

2006 

Kidney (Renal) 

25 9 in TAC 3 in CNI, 13 in CsA 

Range: 14-60y 

64 NR Cyclosporine 

Tacrolimus 

Creatinine 
107

Table 28. Influence of the concomitant use of calcineurin inhibitors on the utility of monitoring mycophenolic acid in patients w

transplant (continued) 

Study Organ n Age % Male Race Medications Health Outcom

Reported 

Okamoto492005 

Kidney (Renal) 

67 Mean: 

38+/-14y 

57 NR Cyclosporine n=35 

Tacrolimus n=32 

Acute rejection, advevents (CMV, Varicedisorder) within 2 weafter transplantation Results for Tac treatgroup vs CsA treate

Pawinski64

2006 

Kidney (Renal) 

33 Range: 

17–62y Mean: 48y 

52.9 NR Cyclosporine 

Tacrolimus Prednisone 

acute rejection, leuccell count, hemotocrvalues, serum creat

Ringe107

2001 

Liver 30 51.9 (15-66)y 70 NR Tacrolimus Acute rejection 

Diarrhea 

Sugioka76

2006 

Kidney (Renal) 

83 Group 1: 63 Group 2: 20 

Range: MPA group: 7-69y, PSL group: 11–66y 

MPA group: 65.1 PSL group: 55 both: 62.7 

NR Cyclosporine 

Tacrolimus Prednisone 

Leukopenia, Diarrhe
108

Table 28. Influence of the concomitant use of calcineurin inhibitors on the utility of monitoring mycophenolic acid in patients w

transplant (continued) 

Study Organ n Age % Male Race Medications Health Outcom

Reported 

Tredger40

2004 

Liver 147 

adults 63 children 

Median adults: 50.1y children: 3.5y Range adults: 6.9-71.8y Range children: 0.3-19.5y 

adults: 53.1 children: 49.2 

NR Cyclosporine 

Tacrolimus 

Acute rejection, all gastrointestinal side low total white cell cleucopenia, neurologepisodes, all infectio(bacterial, fungal another adverse event

Tsaroucha24

2000 

Kidney (Renal) Liver Small bowel 

Liver: 83 Small bowel: 15 Kidney: 25 

Mean: liver: 41.36 +/- 4.56y; small bowel: 18.69 +/- 3.88y; kidney: 44.25 +/- 2.70y 

Liver: 70; Small bowel: 40; Kidney: 52 

NR Tacrolimus 

Steroids 

Rejection, graft survpatient survival 

Weber63

2006 

Kidney (Renal) 

79 condition 1: 54 condition 2: 25 

Range: German study: 3.17-16.0y, suspension trial: 1.0-16.0y 

German study: 61.1, suspension trial: 68.0, both: 63.3 

NR German study: 

Cyclosporine Methylprednisolone Corticosteroids Suspension trial: Cyclosporine Prednisone 

Acute rejection, side such as leukopenia infections 
109

Table 28. Influence of the concomitant use of calcineurin inhibitors on the utility of monitoring mycophenolic acid in patients w

transplant (continued) 

Study Organ n Age % Male Race Medications Health Outcom

Reported 

Zakliczynski 70 2005 Heart (Cardiac) 76 Mean: 41.9 +/- 16y 72 NR Cyclosporine Tacrolimus 

Prednisone Azathioprine 

Gastrointestinal tracirritation (diarrhea, nvomiting, epigastric leukopoenia, anemia 
110

Table 29. Influence of the concomitant use of other medications on the utility of monitoring mycophenolic acid in patients who r

transplant 

Study Organ n Age % Male Race Medications Health Outcomes Reported 

Borrows 69

2005 

Kidney (Renal) 

117 Mean: 

46 +/- 9y Range: 37-55y 

58.1 White 55.6% 

Indo-Asian 23.1 AfroCarib 17.9% Other 3.4% 

Tacrolimus Methylprednisolone Prednisone 

Infective diarrhea, patient survival, graft survival, biopsy proven acute rejection 

Treatmciproflowas asin MPA Treatmantibioand caeffect. No asspredosuse of sulfategancic

Kreis502000 

Kidney (Renal) 

78 Condition 1: SIR: 40 Condition 2: CsA: 38 

SIR: 43.5 +/- 10.9y (22-62); CsA: 42.9 +/- 11.4y (18-60) 

SIR: 70 CsA: 71 

NR Cyclosporine 

Corticosteroids Sirolimus 

Acute rejection rate at 12 months, graft survival, patient survival, renal function Compares Sirolimus group to Cyclosporin group 

Averagwere ssirolimMPA pwere ssirolim

Abbreviations: AUC=Area-under-the–concentration-time curve, CMV=Cytomegalovirus, CNI=Calcineurin Inhibitors, CsA=Cyclosporin A, GI=Gastro

MMF=Mycophenolate Mofetil, MPA=Mycophenolic Acid, MPAG=Mycophenolic Acid Glucuronide, NR=Not Reported, PK=Pharmacokinetic, PSL=P

TAC=Tacrolimus, y=Years
111

Table 29. Influence of the concomitant use of other medications on the utility of monitoring mycophenolic acid in patients who r

transplant (continued)

Study Organ n Age % Male Race Medications Health Outcomes Reported 

Merkel222005 

Kidney (Renal) 

35 Mean: 

44 +/- 13.6y Range: 13–63y 

68.6 NR Cyclosporine 

Corticosteroids Prednisone 

Kidney function (concentration of serum creatinine), rejection, adverse effect (CMV infection) 

No effeor furopredosPositivxipamMPA pA negadiltiazeconce

Mudge 65

2004 

Kidney (Renal) 

45 Mean: 

45.2 +/- 13.2y 

55 White 98% Cyclosporine 

Tacrolimus Prednisone 

Toxicity (GI, hematologic, infectious adverse events), biopsy-proven acute rejection (defined according to Banff 1997 criteria) 

No sigsuppleMMF tfrequeleucopinfectiointolerAUC 

Wolfe781995 

Kidney (Renal) 

12 Mean: 

36 +/- 13y Range: 20 to 57y 

100 NR Cyclosporine 

Prednisone Ganciclovir in 2 arms, one arm alone and 1 arm combined with MMF Azathioprine 

potential drug interaction between MPA and ganciclovir, creatinine clearance 

PK paMPAG additio
112

Table 30. Influence of comorbidity on the utility of monitoring mycophenolic acid in patients who receive a solid organ transplan

Study Organ n Age % Male Race Medications Health Outcomes Reported 

Behrend251997 

Kidney (Renal) 

57 NR NR NR Cyclosporine 

Corticosteroids 

graft function dialysis adverse events infections 

No effect of graon MPA conceIncrease of MPgraft function. 

Brunet66

2006 

Liver 15 Range: 

29 – 66y 

60 NR Tacrolimus 

Methylprednisolone Daclizumab 

Acute rejection No significant c

function and MPAUC. 

Cattaneo 18

2001 

Kidney (Renal) 

46 Range 

19-61y 

63 NR Cyclosporine 

Prednisone CSA Neoral 

Creatinine Anemia Diarrhea Infections 

MPA predose cAUC0-12 were po

significantly corcreatinine clear

Johnson1231998 

Kidney (Renal) 

31 Mean for 

groups 1-5 44.5 +/- 15.9y, 41.7 +/- 10.3y, 43.8 +/- 10.8y, 45.3 +/- 15.0y, 45.3 +/- 8.5y 

Mean for Groups 1-5 83.3, 66.6, 100, 57.1, 66.6 

6 whites in group 1 & 2, 3 white and 3 black in group 3, 6 white and 1 native American in group 4, 3 white 1 black and 2 native Americans in group 5 

None GFR MPA clearance 

with changes in 

as GFR decreacorrelated with Clearance of Munaffected by hduring hemodiathan 10% of the 

Abbreviations: AUC=Area-under-the-concentration-time curve, Cmax=Maximum Serum or Plasma Concentration, GFR=Glomerular Filtration Rate, M

MPAG=Mycophenolic Acid Glucuronide, NR=Not Reported, y=Years
113

Chapter 4. Discussion 

Discussion of the Evidence for the Key Questions 

Question 1. What is the Evidence That Monitoring Mycophenolic Acid 

in Patients who Receive a Solid Organ Transplant Results in a Lower 

Incidence of Transplant Rejections and Adverse events Compared to 

Patients who are not Monitored? 

Only three studies addressed this question. The first, by Meiser et al.,7,8 was really two case 

series reported together. The study was not designed to compare monitoring versus no 

monitoring, so the authors did not report important comparative data. For example, there was no 

presentation of mean plasma predose concentrations for concentration controlled patients who 

did not have rejection, nor was there a statistical comparison of intra- or inter-group differences. 

Therefore, one cannot conclude from this study that outcomes or adverse events were affected by 

monitoring versus no monitoring. The second study, by Flechner et al.,9

 found no evidence to 

suggest that monitoring is associated with a lower incidence of rejection. In contrast, there was 

evidence to suggest that monitored patients could have a lower incidence of certain 

gastrointestinal adverse events. However, the evidence regarding rejection and gastrointestinal 

problems could have been confounded by starting dose. The initial dose of MMF 

(Mycophenolate Mofetil) was different (2 g in the fixed dose group and 1 g in the monitored 

group), so any potential effect of a higher starting dose in the monitored group could have been 

obscured as a result of the study design. As well, more gastrointestinal adverse events might 

have occurred in the fixed dose group regardless of monitoring because there is evidence of a 

positive association between larger MMF doses and adverse events.12

The third study,10 the first published randomized controlled trial (RCT) to compare monitoring 

versus no monitoring of mycophenolic acid (MPA) in any patient group, found a lower incidence 

of treatment failures (driven primary by a lower incidence of acute rejections) in the monitored 

(concentration-controlled) group. Although the RCT suggests a potential benefit for monitoring, 

it is limited to adult kidney transplant patients, so the efficacy of monitoring in other patient 

populations is still unknown. Likewise, the clinical applicability of the trial’s limited area under 

the curve (AUC) sampling strategy, or the applicability of the 40 mg·h/L MPA target dose, to 

these other populations is also unknown. 

Two further RCTs comparing concentration-controlled versus fixed dose patients have, at the 

time of this report, been completed yet not published. Some of the data from these trials are 

publicly available in abstract form. The first RCT is the Opticept study from the United States 

(Roche protocol number ML 17225).124-126 This is a 2 year, open label RCT in kidney transplant 

patients designed to evaluate fixed dose MMF (1 g BID) versus concentration-controlled MMF 

(predose-based dose adjustments of 1.3 μg/mL or more in cyclosporine treated patients and 1.9 

μg/mL in tacrolimus treated patients). The primary outcome is renal function measured as mean 

percent change in calculated GFR (Glomerular filtration rate). So far, the investigators have 

reported that baseline characteristics and renal function were similar between groups in a total 
114

sample of 522 persons. Personal correspondence with one of the study investigators (Roy 

Bloom) and Roche indicate that no results have been published in peer reviewed journals. As 

well, no timelines were available with respect to when further details of the study might be 

published. 

The Fixed Dose Concentration Controlled (FDCC) RCT127-129 is a multicenter RCT 

conducted in Europe, Canada, South America, Asia, and Australia. Kidney transplant patients 

(n=901) were randomized to fixed dose MMF (2 g daily for adults, 1.2 g daily per square meter 

for children) or concentration controlled MMF based on a target MPA AUC0-12 range of 30 to 60 

h.mg/L. The primary outcome was a composite of patients who suffered any of the following: 

biopsy proven acute rejection, graft loss, death, or discontinuation of MMF therapy. According 

to personal correspondence with lead author Teun van Gelder, the main results have been 

submitted to the Lancet. The results from a substudy of the FDCC trial have been published.77 

In the substudy, which reports on 290 patients, 147 received the fixed dose and 143 received the 

concentration controlled dose. The purpose of the substudy was to examine the incidence of 

diarrhea. The patients were further divided by type of concomitant therapy: cyclosporine and 

MMF (n=56 fixed dose; n=54 concentration-controlled) or tacrolimus and MMF (n=91 fixed 

dose; n=89 concentration controlled). Within the cyclosporine/MMF group and the 

tacrolimus/MMF group, there was no difference in the number of cases of diarrhea between 

fixed or concentration controlled patients (p>0.05). When the groups were compared to one 

another, the incidence of diarrhea was higher in the tacrolimus/MMF group (n=69 versus n=17 in 

the cyclosporine/MMF group [p<0.001]). MPA AUC0-12 values did not differ between patients 

who suffered diarrhea and patients who did not (p>0.05). 

While the results of these other two multicenter studies are being anxiously awaited, it should 

be noted that the study populations involve kidney transplant recipients, so the results may not be 

directly applicable to other solid organ transplant subpopulations. Certainly, RCTs in these other 

subpopulations are warranted before the key question can be more fully answered. 

Question 2. Does the Incidence Differ by any of the Following? 

2a: MPA Dose and Dose Frequency 

Overall, the evidence to support an association between MMF dosage and rejection is 

outweighed by the evidence against. However, an equal number of studies supported and refuted 

the association between MMF dosage and adverse events. Unfortunately, most of the evidence 

was in the form of case series. Furthermore, even the relatively few higher quality studies (e.g., 

cohort studies) were not designed to address whether MMF dosage is associated with rejection or 

adverse events. These factors, coupled with the diversity of other variables in the studies (e.g., 

concomitant medications, different lengths of followup, specific adverse events evaluated) make 

it difficult to provide a clear answer to the question. What is direly needed are RCTs that 

compare patients who are monitored to patients who are not monitored. Ideally, these trials 

would permit comparisons at different fixed doses and at different targets for concentration 

control. 
115

2b: Type of MPA (mycophenolate mofetil [CellCept®], enteric-coated 

mycophenolate sodium [Myfortic®]) 

The recently introduced, enteric-coated, delayed release formulation of MPA (i.e., entericcoated mycophenolate sodium (ECMPS)) was designed to reduce upper gastrointestinal adverse 

events. ECMPS delivers the same MPA exposure (AUC) as MMF and is therapeutically 

equivalent, but leads to higher C0 concentrations.130 None of the included studies directly 

compared ECMPS with MMF. Studies that were not helpful in answering question 2b included 

those without control group, e.g. with all patients switched from MMF to mycophenolate 

sodium. Due to small numbers, adverse events or rejection events were not observed or could 

not be correlated with PK parameters in many studies, so question 2b could not be answered. 

Clinicians should be aware of the potential for higher predose plasma or serum 

concentrations (C0) with ECMPS compared to MMF. Full AUCs are not expected to be different 

between the two formulations, but are too difficult to use in standard practice situations. Predose 

concentrations or abbreviated sampling strategies are more realistic, but due to the delayed 

absorption of ECMPS, they will have to be validated separately from MMF. Future randomized 

concentration-controlled trials comparing no monitoring to monitoring with different target PK 

parameters could establish therapeutic concentrations for mycophenolate sodium and evaluate 

the utility of monitoring at the same time. 

Question 3a: Does the Incidence Differ by Total Versus Free MPA, 

Albumin, Metabolites, Genetic Differences or by Analytical Method of 

MPA Monitoring? 

Does the Incidence Differ by Total Versus Free MPA or Albumin? 

Only free, protein unbound drug molecules are available for receptor binding. Therefore, 

measurements of free MPA (fMPA) may theoretically be expected to correlate better with 

outcomes than total MPA. However, none of the included studies confirmed this hypothesis, 

although free (not total) MPA was found to be associated with infections and haematological 

adverse events.13,14,17 Thus, there is potential for the utility of fMPA monitoring, but this has yet 

to be demonstrated in an RCT. Many of the studies in this report showed that impaired renal 

function and hypoalbuminemia coincide with elevated mycophenolic acid glucuronide (MPAG) 

and fMPA, but not total MPA. The mechanisms involved are complex. In renal failure, MPAG 

excretion is decreased, the accumulated metabolite displaces MPA from albumin, and the added 

fMPA is available not only for therapeutic or toxic effects, but also for hepatic clearance. 

Measures of total MPA do not reflect these processes and might even be decreased. Given the 

added complexity and limited availability of fMPA testing, an alternative would be to measure 

total MPA while taking renal function and serum albumin into account. Recently, however, 

Roche has introduced an Inosine 5’-monophosphate dehydrogenase (IMPDH) based assay for 

free and total MPA. A CEDIA assay is now available from Microgenics. 
116

Does the Incidence Differ by Genetic Differences or Metabolite 

Concentrations? 

The pharmacogenetic study by Naesens et al.79 showed that carriers of the two MRP2 

(multidrug resistance protein) SNPs (single nucleotide polymorphisms) were protected from 

reduced MPA exposure in mild liver dysfunction. The other genetic study, by Satoh et al.,30

found associations between MPA and genes, genes and diarrhea, and MPA and rejection. The 

clinical relevance of both studies is unclear, as they do not suggest how monitoring of MPA 

could be augmented to prevent rejection or adverse events. The biochemical mechanisms are not 

well enough understood and genetic screening for the mentioned polymorphisms does not seem 

warranted. More basic and clinical research appears necessary. 

The studies regarding metabolites yielded few positive results. The fat malabsorption 

results,16 based on five patients, apply to a very specialised population. The only other 

significant associations were those between AcMPAG (acyl glucuronide metabolite of 

mycophenolic acid), MPAG, and anemia, but not to other adverse events or efficacy endpoints.15 

Monitoring of metabolites cannot be generally recommended based on these results. The 

pharmacokinetics of MPA is very complex, involving enterohepatic recirculation, competition of 

parent drug and MPAG for albumin binding, many drug-drug interactions and other 

complicating factors. Although the active metabolite (AcMPAG) may hold some promise in 

predicting toxicities, the mechanisms leading to adverse events, especially GI effects, are not yet 

understood and should be studied in the laboratory. Larger, randomized trials are necessary to 

establish the utility of monitoring MPA and its metabolites. 

Does the Incidence Differ by Assay Method? 

In two studies,26,27 HPLC (high-performance liquid chromatography) and EMIT (enzymemultiplied immunoassay technique) performed similarly well in the assessment of acute rejection 

risk in pediatric kidney transplant patients. As expected, EMIT cut off values were higher than 

those derived from HPLC measurements. This is because immunoassays often show a positive 

bias compared to more specific chromatographic techniques. As well, the EMIT for MPA cross 

reacts with AcMPAG, an active metabolite of MPA.119 Theoretically, EMIT could be 

advantageous over HPLC because it might reflect total immunosuppressive activity better, 

although this is not certain because cross reactivities are concentration dependent, and the two 

studies did not find EMIT to be superior. Potentially higher cut off values for EMIT mean that 

target ranges for total MPA AUC0-12 or C0 will have to be derived separately for HPLC and 

EMIT. 

The general implications of the findings are difficult to assess. Only two studies26,27 directly 

compared HPLC and EMIT; the study populations in both studies were pediatric patients. It 

remains to be seen whether diagnostic sensitivities and specificities would differ between 

methods in other populations. In one study,27 the age and sex distributions of pediatric patients 

were not provided, so it was difficult to know exactly to whom the diagnostic sensitivities and 

specificities were applicable. As well, there is currently no information about the comparative 

merits of HPLC or EMIT in conjunction with other assay methods, such as HPLC-MS, because 

no study was undertaken to make such comparisons. 

Adverse events were considered in one study26 and MPA PK (pharmacokinetic) parameters 

were not found to predict them, regardless of assay method. However, there is some evidence in 
117

this report that PK parameters can distinguish between persons with and without adverse events. 

Perhaps the findings apply only to the specific profile of pediatric patients enrolled in the study. 

Another possibility is the potential for bias. Weber et al.26 did not explain the basis upon which 

their patients were chosen, thus raising the issue of selection bias. Verification bias may also 

have been present because some patients did not undergo biopsy, nor was there any reporting of 

stratification according to the factors that triggered biopsy. 

Another issue with the two studies26,27 that are pertinent to Question 3aii was the lack of 

clarity concerning how the operating points on the ROC (receiver operator characteristic) curves 

were chosen. Other choices of decision levels and their corresponding sensitivity/specificity 

pairs may have been more appropriate, depending on the prior probability of rejection, the 

importance of correct classification, and the relative undesirability of false positive or false 

negative errors. 

Ultimately, since the goal of monitoring is the prevention (not diagnosis) of rejection and 

adverse events, the utility of monitoring will have to be assessed in trials designed to study this 

goal. A factorial trial would be appropriate to study monitoring versus not monitoring in 

conjunction with the efficacy of measuring MPA using different assay methods, including the 

new assays for total and free MPA mentioned above. Alternatively, reference therapeutic PK 

parameters for different assay methods could first be derived from observational studies and then 

tested in an RCT. A similar strategy may apply for all key questions. 

3b: Does the Incidence Differ by Method of MPA Monitoring (Full AUC 

or Limited Sampling Strategies [i.e., Predose Concentrations, 2 hour 

Post Dose Concentrations, Other])?

Overall, the evidence to support an association between full AUC (AUC0-12) and rejection 

outweighs the evidence against. The opposite is true for the association between full AUC and 

adverse events. There are more studies showing that predose (C0, Cmin, or C12) compared to full 

AUC measurements are associated with both rejection and adverse events, but there are an even 

greater number of studies demonstrating that trough has no association. Equal numbers of 

studies demonstrate positive versus no associations between monitoring using other limited 

sampling strategies and rejection, but when adverse events are considered there are more studies 

showing a lack of association rather than an association.

Since full AUC measurements are cumbersome and impractical to use clinically, and more 

studies demonstrate the lack of utility of trough in discriminating between patients with and 

without rejection or adverse events, we are left to consider other limited sampling strategies. To 

date, C2 has not been well studied and there appears to be no consensus regarding the utility of 

other limited sampling strategies in discriminating between rejectors and non rejectors. However, 

there are three times as many studies that demonstrate the lack of utility of other limited 

sampling strategies in predicting adverse events. 

The evidence for answering this question is limited by the objectives of the included studies. 

Most of the studies were observational or case series designs developed with the intention of 

studying the biological or pharmacological effects of MMF dosing or MMF in combination with 

a calcineurin inhibitor. Some earlier exploratory studies were undertaken to obtain information 

on the associations between PK parameters and dosing, time, or other PK parameters. None of 

the studies were designed to compare the incidence of rejection or adverse events in groups of 

patients whose MMF doses were controlled using different sampling strategies. Although many 
118

studies had multiple sampling strategies measured on the same patients, these measurements 

were not used for dose adjustment. Rather, the authors of these studies sought to examine 

whether mean measurement values were associated with an outcome such as rejection or adverse 

events. These data are hypothesis generating because they can provide insight into the types of 

sampling strategies to use in monitoring, but they do not actually indicate whether monitoring 

and dose adjustment would have an affect on outcomes. 

Question 3b can best be answered with head-to-head (RCT) comparisons of monitoring and 

dose adjustment using different sampling strategies. To date, there is only one published study 

comparing concentration-controlled and fixed dose MMF.10 In the concentration-controlled 

group, the investigators used a 3-sample limited sampling strategy (developed by Bayesian 

techniques) to predict MPA AUC. Although the concentration-controlled group had significantly 

lower treatment failures and acute rejections, there was no significant difference in incidence of 

most adverse events, save for the incidence of herpes infections, which was greater in the 

concentration-controlled group. As eloquently articulated in an editorial accompanying the 

published trial, “One is left to wonder that despite an elegant and elaborate algorithm for dose 

changes, could these same [adverse effect] results have been obtained by simply administering 

higher doses of MMF without MPA monitoring?”131

Question 4. Does the Evidence for Monitoring MPA Differ by any of 

the Following – Age, Gender, Ethnicity, Concomitant use of 

Calcineurin Inhibitors, Concomitant use of Other Medications, 

Comorbidity? 

Across all parts of Question 4, most of the evidence from the literature search did not directly 

address the key question. Studies of direct relevance would have evaluated whether monitoring 

MPA in recipients of solid organ transplants would have led to a lower incidence of rejections or 

adverse events compared to not monitoring, with subanalyses (specified a priori) stratified by 

factors such as age, gender, ethnicity, concomitant use of medications, and comorbidities. To 

date, no such study exists. 

The majority of included studies focused on adults and kidney transplant recipients. Few 

studies involved children, the elderly, or other solid organ transplants. Study findings were 

difficult to compare because measures of MPA in plasma or serum sometimes exhibit large intraand inter-patient variability over time post transplant. Moreover, the factors of concern (e.g., 

age) in this question were not consistently addressed in all of the included studies. Inconsistency 

was also a hallmark of outcome definition or selection, thereby further detracting from 

comparability. For example, rejection was inconsistently defined, sometimes clinically via Banff 

criteria and sometimes using surrogate endpoints such as GFR or serum creatinine. A consistent 

basket of adverse events was also not the norm. Many studies looked at particular adverse 

events (e.g., gastrointestinal, liver dysfunction) or did not clearly define the types of adverse 

events that were under examination. Some published studies, primarily rapid communications 

such as the work of Behrend et al.,25 provided limited raw data to support descriptive results and 

conclusions. 

Based on the evidence that could be gleaned from the included studies, certain patient 

demographics appeared to influence MPA PK parameters. Within pediatric populations, the 

evidence suggested that younger children may require a higher MMF dose to achieve a specified 

MPA concentration. Similarly, the evidence suggests that the elderly have lower MPA exposure 
119

compared to younger adults receiving the same dose of MMF. However, the bulk of the evidence 

indicated no association between patient age and MPA PK parameters in general (i.e., over all 

age ranges without stratification into pediatric and adult populations). Regarding gender, the 

evidence suggested AUC0-12 and predose concentrations might be higher in women, but the 

impact of these findings for monitoring rejection or adverse events was not studied. Race and 

ethnicity did not appear to influence PK parameters. 

Calcineurin inhibitors are co-administered frequently with MMF and many studies examined 

the relationship between these drugs and MPA PK parameters. The evidence found that 

exposure to MPA is higher in patients receiving tacrolimus compared to cyclosporine, with lower 

doses of MMF required in combination with tacrolimus to achieve adequate MPA exposure. This 

difference is explained by the inhibition of the enterohepatic circulation of MPA by 

cyclosporine. Concomitant use of medications not only influences the MPA exposure but also 

may affect the utility of therapeutic drug monitoring (TDM). If a solid organ transplant recipient 

is receiving four different immunosuppressants with a low rejection risk, the overall 

immunosuppressant effects depend to a much lesser degree on the correct dosing of MPA, 

whereas in a regimen with only two immunosuppressants and a higher risk of rejection, the 

overall adequacy of immunosuppression depends heavily on the correct dosing and exposure of 

MPA. 

The effect of renal function on MPA PK parameters was addressed in a number of studies, but 

the findings were inconsistent and inconclusive. 

Question 5. What is the Short- and Long-Term Cost-Effectiveness of 

Avoiding Acute Rejection due to MPA Monitoring? 

The published literature contains no data on the cost effectiveness of monitoring versus no 

monitoring in solid organ transplants. Therefore, it is not possible to answer this key question. 

At the time this report is being written, the authors of the lone published RCT on monitoring 

versus no monitoring10 report that an economic evaluation of their trial results is ongoing. These 

results, once published, will be an important addition to the literature. For a monitoring strategy 

to be cost-effective, the additional costs of implementing the monitoring protocol would have to 

be exceeded by the savings associated with treating fewer rejections or adverse events. From the 

perspective of a public or private health insurer that is considering whether to reimburse the cost 

of monitoring, it is not sufficient to simply look at cost data. Effectiveness data (e.g., quality 

adjusted life years [QALYs]) should also be considered and evaluated using standard methods of 

cost effectiveness analysis.100 The result of such an analysis would be to obtain an incremental 

cost per unit of effect (e.g., cost per QALY). This ratio can be used to compare monitoring with 

other competing healthcare programs, thereby allowing insurers to determine which program is 

most effective per unit of cost. Such information can be used to help make decisions about 

which program(s) to reimburse. 

Limitations of This Evidence Report 

Only English language, published studies were included in the report. The available budget 

and timelines limited the McMaster University Evidence-based Practice Center’s (MU-EPC’s) 

ability to obtain, translate, and abstract non English or unpublished studies. In addition, study 

authors were not contacted to obtain supplemental data that were not presented in the published 
120

articles. It has been the MU-EPC’s experience that the majority of authors do not respond in a 

timely fashion, if at all, to requests for information. These omissions may have introduced 

publication bias into this evidence report. 

Virually all of the studies involve MMF, not ECMPS. The generalizability of MMF data to 

ECMPS should be handled with extreme caution because differences in absorption kinetics 

make, it difficult to substitute algorithms developed for limited sampling strategies in MMF to 

ECMPS. In addition, the utility of predose concentration measurements may be even more 

limited for persons receiving ECMPS than for persons receiving MMF because the entericcoated formulation is particularly prone to delays in gastric emptying time. As a result, very 

high morning predose concentrations can be encountered. 

The evidence report contains all of the relevant literature to address the key questions up to 

and including October 2007. This means that new and potentially important studies published 

after this date will not be included unless a future update of the report is commissioned. 

Conclusions 

The state of knowledge about therapeutic drug monitoring of MPA in solid organ transplants 

is still in its infancy. This is especially so for organs other than the kidney because the 

overwhelming majority of published studies involve kidney transplant patients. There is direct 

evidence from only one study10 to suggest that monitoring would reduce the incidence of 

rejection in adult kidney transplant patients. Two soon to be published trials (Opticept, FDCC) 

will supplement this limited evidence, but many issues will remain outstanding. These issues 

include the optimal method of MPA monitoring. The most complete and most studied method is 

the full AUC (AUC0-12), but this procedure requires at least eight blood samples over a 12 hour 

dose interval and is therefore impractical to use in most clinical settings. Evidence for the utility 

of limited sampling strategies (e.g., predose [C0, Cmin, C12]) is equivocal at best and largely based 

on case series or observational studies whose primary purpose was something other than to 

compare strategies. Other limited sampling strategies (e.g., C2, multiple sample strategies, etc.) 

have not been studied well enough to assess their utility for monitoring. 

Another issue is the lack of an obvious MPA target concentration to govern dose adjustment. 

The selection of such a concentration depends on the sampling strategy and may be frustrated by 

the wide intra-patient variability in MPA plasma concentration time profiles, especially if the 

influence of time after transplantation is not accounted for. Even if a standardized target 

concentration can be agreed upon, there are too few studies to guide the choice of assay or 

suggest the best frequency for measuring MPA in the plasma or serum. At this point, there is no 

evidence to even suggest whether assay type matters. 

The utility of monitoring MPA is further muddled by the fact that resolutions to all of the 

aforementioned issues may differ by type of drug (MMF, ECMPS), dose, population 

characteristics (adult, pediatric), comorbidity, concomitant medications, and type of organ 

transplanted. There is certainly evidence to suggest that these items matter (e.g., physicians 

targeting MPA predose concentrations must note the existence of higher morning C0

concentrations with ECMPS130), but the literature provides no clear guidance on how to 

operationalize them clinically. Furthermore, there is little data available on the long term 

pharmacokinetics of MPA. The extent to which changes in pharmacokinetic parameters over 

time post transplant can affect the utility of TDM needs to be the subject of investigation. 
121

Another knowledge gap is in the area of economic evaluation. No published study has 

contained an examination of whether monitoring is cost effective versus no monitoring. The 

results of such an analysis could influence the reimbursement decisions of private or public 

health insurers. These decisions are important because they affect patient access to treatment. 

Quality is also an issue. Reporting of some essential features of RCT design (e.g., method of 

randomization, blinding) and observational study design (e.g., blinding) was lacking in most 

studies. Additionally, only 28 of 75 observational studies reported attempts to control 

confounding. Since none of the observational studies contained direct evidence to address the 

key questions, the studies can be regarded as hypothesis generating rather than hypothesis 

confirming. The quality issue further reinforces the notion of hypothesis generation versus 

confirmation. Studies with quality challenges may not have valid results because of bias and 

confounding. Consequently, the results of these studies should be verified in future research, 

preferably using well-designed RCTs. 

Overall, the published evidence on MPA monitoring is inconclusive, with some studies 

suggesting potential benefits and other studies suggesting no benefit. This makes the issuance of 

clinical recommendations difficult. There is no evidence, except for one published RCT, to 

suggest that monitoring is more or less beneficial than not monitoring. Until there is more 

evidence on the utility of routine MPA monitoring in solid organ transplant recipients, patients, 

clinicians, and other stakeholders (e.g., public and private insurers) will have to decide on a case 

by case basis whether the possible but uncertain benefits are worth the extra time and expense of 

monitoring. 
123

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transplantation. Exp Clin Transplant 2005;3(1):293-

300. 

104. Pape L, Ehrich JH, Offner G. Long-term follow-up of 

pediatric transplant recipients: mycophenolic acid 

trough levels are not a good indicator for long-term 

graft function. Clin Transplant 2004;18(5):576-9. 

105. Wollenberg K, Krumme B, Schollmeyer P, et al. 

Pharmacokinetics of mycophenolic acid after renal 

transplantation. Transplant Proc 1998;30(5):2237-9. 

106. Brunet M, Martorell J, Oppenheimer F, et al. 

Pharmacokinetics and pharmacodynamics of 
128

mycophenolic acid in stable renal transplant recipients 

treated with low doses of mycophenolate mofetil. 

Transpl Int 2000;13(Suppl 1):S301-S305 

107. Ringe B, Braun F, Schutz E, et al. A novel 

management strategy of steroid-free 

immunosuppression after liver transplantation: 

efficacy and safety of tacrolimus and mycophenolate 

mofetil. Transplantation 2001;71(4):508-15. 

108. Naito T, Shinno K, Maeda T, et al. Effects of 

calcineurin inhibitors on pharmacokinetics of 

mycophenolic acid and its glucuronide metabolite 

during the maintenance period following renal 

transplantation. Biol Pharm Bull 2006;29(2):275-80. 

109. Gonzalez-Roncero FM, Gentil MA, Brunet M, et al. 

Pharmacokinetics of mycophenolate mofetil in kidney 

transplant patients with renal insufficiency. 

Transplant Proc 2005;37(9):3749-51. 

110. Weber LT, Lamersdorf T, Shipkova M, et al. Area 

under the plasma concentration-time curve for total, 

but not for free, mycophenolic acid increases in the 

stable phase after renal transplantation: a longitudinal 

study in pediatric patients. German Study Group on 

Mycophenolate Mofetil Therapy in Pediatric Renal 

Transplant Recipients. Ther Drug Monit 

1999;21(5):498-506. 

111. Johnson AG, Rigby RJ, Taylor PJ, et al. The kinetics 

of mycophenolic acid and its glucuronide metabolite 

in adult kidney transplant recipients. Clin Pharmacol 

Ther 1999;66(5):492-500. 

112. Weber LT, Shipkova M, Lamersdorf T, et al. 

Pharmacokinetics of mycophenolic acid (MPA) and 

determinants of MPA free fraction in pediatric and 

adult renal transplant recipients. German Study group 

on Mycophenolate Mofetil Therapy in Pediatric Renal 

Transplant Recipients. J Am Soc Nephrol 

1998;9(8):1511-20. 

113. Shaw LM, Mick R, Nowak I, et al. Pharmacokinetics 

of mycophenolic acid in renal transplant patients with 

delayed graft function. J Clin Pharmacol 

1998;38(3):268-75. 

114. Yatscoff RW, Aspeslet LJ. The monitoring of 

immunosuppressive drugs: a pharmacodynamic 

approach. Ther Drug Monit 1998;20(5):459-63. 

115. Morgera S, Budde K, Lampe D, et al. Mycophenolate 

mofetil pharmacokinetics in renal transplant recipients 

on peritoneal dialysis. Transpl Int 1998;11(1):53-7. 

116. Morgera S, Neumayer HH, Fritsche L, et al. 

Pharmacokinetics of mycophenolate mofetil in renal 

transplant recipients on peritoneal dialysis. Int J Clin 

Pharmacol Ther 1998;36(3):159-63. 

117. Jain A, Kashyap R, Dodson F, et al. A prospective 

randomized trial of tacrolimus and prednisone versus 

tacrolimus, prednisone and mycophenolate mofetil in 

primary adult liver transplantation: a single center 

report. Transplantation 2001;72(6):1091-7. 

118. Staskewitz A, Kirste G, Tonshoff B, et al. 

Mycophenolate mofetil in pediatric renal 

transplantation without induction therapy: results after 

12 months of treatment. German Pediatric Renal 

Transplantation Study Group. Transplantation 

2001;71(5):638-44. 

119. Shipkova M, Schutz E, Armstrong VW, et al. 

Overestimation of mycophenolic acid by EMIT 

correlates with MPA metabolite. Transplant Proc 

1999;31(1-2):1135-7. 

120. Lu YP, Lin B, Liang MZ, et al. Correlation of 

mycophenolic acid pharmacokinetic parameters with 

side effects in Chinese kidney transplant recipients 

treated with mycophenolate mofetil. Transplant Proc 

2004;36(7):2079-81. 

121. Ulinski T, Perrin L, Morris M, et al. Autoimmune 

polyendocrinopathy-candidiasis-ectodermal dystrophy 

syndrome with renal failure: impact of posttransplant 

immunosuppression on disease activity. J Clin 

Endocrinol Metab 2006;91(1):192-5. 

122. Wang CX, Meng FH, Chen LZ, et al. Population 

Pharmacokinetics of Mycophenolic Acid in Senile 

Chinese Kidney Transplant Recipients. Transplant 

Proc 2007;39(5):1392-5. 

123. Johnson HJ, Swan SK, Heim-Duthoy KL, et al. The 

pharmacokinetics of a single oral dose of 

mycophenolate mofetil in patients with varying 

degrees of renal function. Clin Pharmacol Ther 

1998;63(5):512-8. 

124. Bloom R, Naraghi R, Cibrik D, et al. OPTICEPT 

trial: Interm results of 6-month efficacy and safety of 

monitored mycophemolate mofetil (MMF) in 

combination with CNI in renal transplantation. Am J 

Transplant 2006;6(s2):344 

125. Meier-Kriesche HU, Gaston R, Bloom R, et al. 

Opticept trial: Interim analysis of renal function after 

12 months of monitored myeophenolate mofetil in 

combination with CNI in renal transplantation. Am J 

Transplant 2007;7(Suppl 2):439 

126. Gaston R, Shah T, Bloom R, et al. Opticept trial: 

interim results of 12-month efficacy and safety of 

monitored mycophenolate mofetil (MMF) in 

combination with CNI in renal transplantation. Am J 

Transplant 2007;7(Suppl 2 1163):445 

127. Heller T, Armstrong V, Brandhorst G, et al. Plasma 

concentrations of myocophenolic acid acylglucuronide 
129

related to diarrhoea. Interm results from the FDCC 

study. Am J Transplant 2006;6(s2):344-5. 

128. van Gelder T. The effects of delayed graft function on 

mycophenolate mofetil pharmacokinetics. Am J 

Transplant 2007;7(Suppl 2):162 

129. van Agteren M, van Gelder T. Polymorphism in the 

ABCB1 (MDR1) gene do not explain the interindividual variability in mycophenolate mofetil 

pharmacokinetics. Am J Transplant 2007;7(Suppl 

2):535 

130. Budde K, Tedesco-Silva H, Pestana JM, et al. 

Enteric-coated mycophenolate sodium provides higher 

mycophenolic acid predose levels compared with 

mycophenolate mofetil: implications for therapeutic 

drug monitoring. Ther Drug Monit 2007;29(3):381-4. 

131. West-Thielke P, Kaplan B. Therapeutic monitoring of 

mycophenolic Acid: is there clinical utility? Am J 

Transplant 2007;7(11):2441-2. 
130
131

List of Acronyms/Abbreviations 

AcMPAG Acyl Glucuronide Metabolite of Mycophenolic Acid 

AHRQ Agency for Healthcare Research Quality 

AMED Allied and Complementary Medicine 

AUC Area Under the -Curve 

CI Confidence Interval 

CNI Calcineurin Inhibitor 

CMV Cytomegalovirus 

C0 Predose Trough Serum or Plasma Concentration

CMAX Maximum Serum or Plasma Concentration

ECrCl Estimated Creatinine Clearance 

ECMPS Enteric-coated Mycophenolate Sodium 

EMIT Enzyme-Multiplied Immunoassay Technique 

fMPA Free Mycophenolic Acid 

GFR Glomerular Filtration Rate 

HPLC High-Performance Liquid Chromatography 

HPLC-MS High-Performance Liquid Chromatography-Mass Spectrometry 

HRR Hazard Rate Ratio 

IMPDH Inosine 5'-Monophosphate Dehydrogenase 

LSS Limited Sampling Strategy 

MDR Multidrug Resistance 

MRP Multidrug Resistance Protein 

MMF Mycophenolate Mofetil 

MPA Mycophenolic Acid 

MPAG Mycophenolic Acid Glucuronide 

MU-EPC McMaster University Evidence-Based Practice Center 

OAT Oroanal Transit Time 

OCTT Orocecal Transit Time 

PK Pharmacokinetic 

QUALYs Quality Adjusted Life Years 

RCT Randomized Controlled Trial 

ROC Receiver Operator Characteristic 

RR Relative Risk 

SNP Single Nucleotide Polymorphisms 

SRS Systematic Review Software 

TDM Therapeutic Drug Monitoring 

TEP Technical Expert Panel 

TOO Task Order Officer 

UGT Uridine Diphosphoglucuronosyltransferase 
A-1

Appendix A. Exact Search Strings 

Database: Ovid MEDLINE® 

1. Mycophenolic Acid/ 

2. mmf.ti,ab. 

3. myfortic.mp. 

4. cell?ept.mp. 

5. mycophenol$.mp. 

6. mofetil.mp. 

7. mycofenolate.mp. 

8. or/1-7 

9. exp Kidney Transplantation/ 

10. exp Heart Transplantation/ 

11. exp liver transplantation/ or exp pancreas transplantation/ 

12. exp Lung Transplantation/ 

13. exp Graft Rejection/ 

14. exp Organ Transplantation/ 

15. ((transplant$ or graft) adj4 (kidney or renal or lung$ or cardiac or heart or pancreas or liver 

or organ or reject$ or patient$)).ti,ab. 

16. or/9-15 

17. drug monitoring/ or monitoring, immunologic/ 

18. Dose-Response Relationship, Drug/ 

19. exp Pharmacokinetics/ 

20. (monitor$ or sampl$ or measur$).ti,ab. 

21. or/17-19,20 

22. 16 or 21 

23. 22 and 8 

24. (transplant immunology or transplant infectious disease or transplant international or 

transplantation or transplantation bulletin or transplantation proceedings or transplantation 

reviews or transplantation science).jn. 

25. 24 and 8 

26. 23 or 25 

27. exp *Cell Transplantation/ 

28. 26 not 27 

29. humans/ 

30. animals/ 

31. 29 and 30 

32. 30 not 31 

33. 28 not 32 

Database: EMBASE® 

1. Mycophenolic Acid/ 
A-2

2. mmf.ti,ab. 

3. myfortic.mp. 

4. cell?ept.mp. 

5. mycophenol$.mp. 

6. mofetil.mp. 

7. mycofenolate.mp. 

8. exp Mycophenolic Acid 2 Morpholinoethyl Ester/ 

9. or/1-8 

10. exp organ transplantation/ 

11. exp Graft Rejection/ 

12. Graft Recipient/ 

13. ((transplant$ or graft) adj4 (kidney or renal or lung$ or cardiac or heart or pancreas or liver 

or organ or reject$ or patient$)).ti,ab. 

14. or/10-13 

15. Dose-Response Relationship, Drug/ 

16. drug monitoring/ or monitoring, immunologic/ 

17. exp pharmacokinetics/ 

18. or/15-17 

19. 14 or 18 

20. 19 and 9 

21. (transp sci or transplant immunology or transplant international or transplantation or 

transplantation proceedings or transplantation reviews).jn. 

22. 21 and 9 

23. exp *Stem Cell Transplantation/ 

24. human.sh. 

25. nonhuman.sh. 

26. animal.sh. 

27. animal experiment.sh. 

28. 25 or 26 or 27 

29. 24 and 28 

30. (monitoring or sampling or measur$).ti,ab. 

31. 30 and 9 

32. 31 or 20 

33. 32 or 22 

34. 33 not 23 

35. 34 not 28 

36. 34 and 29 

37. 35 or 36 

Database: EBM Reviews - Cochrane Central Register of Controlled 

Trials® 

1. Mycophenolic Acid/ 

2. mmf.ti,ab. 

3. myfortic.mp. 
A-3

4. cell?ept.mp. 

5. mycophenol$.mp. 

6. mofetil.mp. 

7. mycofenolate.mp. 

8. or/1-7 

9. exp Kidney Transplantation/ 

10. exp Heart Transplantation/ 

11. exp liver transplantation/ or exp pancreas transplantation/ 

12. exp Lung Transplantation/ 

13. exp Graft Rejection/ 

14. exp Organ Transplantation/ 

15. ((transplant$ or graft) adj4 (kidney or renal or lung$ or cardiac or heart or pancreas or liver 

or organ or reject$ or patient$)).ti,ab. 

16. or/9-15 

17. drug monitoring/ or monitoring, immunologic/ 

18. Dose-Response Relationship, Drug/ 

19. exp Pharmacokinetics/ 

20. (monitor$ or sampl$ or measur$).ti,ab. 

21. or/17-20 

22. 16 or 21 

23. 22 and 8 

24. (transplant immunology or transplant infectious disease or transplant international or 

transplantation or transplantation bulletin or transplantation proceedings or transplantation 

reviews or transplantation science).jn. 

25. 24 and 8 

26. 23 or 25 

27. exp *Cell Transplantation/ 

28. 26 not 27 

Database: EBM Reviews - Cochrane Database of Systematic Reviews® 

1. mmf.ti,ab. 

2. myfortic.mp. 

3. cell?ept.mp. 

4. mycophenol$.mp. 

5. mofetil.mp. 

6. mycofenol$.mp. 

7. or/1-6 (34) 

8. ((transplant$ or graft) adj4 (kidney or renal or lung$ or cardiac or heart or pancreas or liver 

or organ or reject$ or patient$)).ti,ab. 

9. (monitor$ or sampl$ or measur$).ti,ab. 

10. 8 or 9 

11. 10 and 7 
A-4

Database: BIOSIS® Previews 

1. TS=(mycophenol*) 

2. TS=transplant* 

3. #2 AND #1 

4. TS=(mycophenol* OR myfortic OR cellcept or mofetil) 

5. CH=mycophenolate mofetil 

6. #5 OR #4 

7. MQ=organ transplantation 

8. TS=((liver OR kidney OR renal OR pancrea* OR heart OR cardiac OR lung OR organ OR 

reject* OR patient) SAME (transplan* OR graft)) 

9. #8 OR #7 

10. 10.#9 AND #6 
B-1 

Appendix B. Forms/Guides 

Level 1 – Title and Abstract Screening 

YES / 

MAYBE 

(continue)

NO 

(stop)

Is a Case 

Series 

(continue) 

1. Is the paper published in English? Clear

2. Is the publication a peer reviewed full 

report of an RCT, cohort study, or casecontrol study (is not a case report, review, 

overview, discussion piece, conference 

report/proceeding, abstract, editorial, or 

letter to the editor)? 

Clear

3. Are outcomes reported for human 

subjects with solid organ transplants? Clear

4. Does the study involve measurement of 

any form of MPA in the blood? Clear

Submit Data 
B-2 

Level 2 – Full Text Screening 

YES 

(continue) 

NO 

(stop)

1. Is this report published in English? Clear

2. Is the publication a peer reviewed full report of an RCT, 

cohort study, case-series or case-control study (is not a 

case report, review, overview, discussion piece, 

conference report/proceeding, abstract, editorial, or letter 

to the editor)? 

Clear

3. Does the study report on humans with solid organ 

transplants as the subjects? Clear

4. Is any form of MPA measured in the blood? Clear

5. Is any form of MPA monitored in the blood (measured 

with the intent of using the result for any action, based on 

the MPA blood level)? Clear

6. Are MPA blood levels associated with any clinical 

health outcome? Clear

7. Is there any indication that this paper may be a 

companion to another publication? Clear

Submit Data 
B-3 

Level 3 – Sorting 

1. Should this paper be included? (check all that apply) 

YES - include this paper 

NO - not a full report of included type of study 

NO - not transplant patients 

NO - MPA not measured 

NO - health outcomes not associated with MPA measured in blood 

2. Is NO answered to any question above?

YES 

NO 

3. Does this study: (check all that apply)

provide data on the dose or dose frequency of MPA? (Review Q2a) 

specify the type of MPA given to the patient? (Review Q2b) 

describe the form of MPA measured in the blood? (Review Q3a) 

describe the time(s) MPA measurements were made? (Review Q3b) 

evaluate any factor affecting MPA monitoring? e.g. age, gender, ethnicity, 

use of calcineurin inhibitors, use of other medications, comorbidity (Review Q4) 

Does this study describe any economic assessment of MPA? (Review Q5) 

Submit Data
B-4 

Level 10 – General Data 

1. Surname of first author 

 

2. Year of publication 

 

3. Country of study 

 

4. Aim of study (<10 words or cut and paste one sentence only) 

 

5. Study design 

 

6. Transplanted organ(s) 

Heart (Cardiac) 

Kidney (Renal) 

Liver 

Lung 

Small bowel 

Other 

 

7. Age (years)

Inclusion requirement 

Mean for entire population 

Range for entire population 

Unsure 

Not reported 

 

8. % male in population

Entire population 

Unsure 

Not reported 

 
B-5 

9. Description of study population other than age, gender, BSA, transplanted 

organ 

 

10. Entered into study, n = 

Entire population 

Condition 1 

Condition 2 

Condition 3 

Condition 4 

Unsure 

Not reported 

 

11. Analyzed, n =

Entire population 

Condition 1 

Condition 2 

Condition 3 

Condition 4 

Unsure 

Not reported 

 

12. Form of MPA given 

Mycophenolate mofetil (MMF, CellCept) 

Mycophenolate sodium (Myfortic - enteric coated, EC - delayed release) 

Other1 

Other2 

Unsure 

Not reported 

 

13. Dose of MPA given 

 
B-6 

14. Prospective dose adjustment planned 

No 

Yes - based on clinical indicators 

Yes - based on MPA (or metabolite) blood levels

Unsure 

 

15. Body weight or body surface area 

Inclusion requirement 

Mean for entire population 

Range for entire population 

Unsure 

Not reported 

 

16. Form of MPA measured

MPA 

MPAG 

AcMPAG 

free MPA 

Bound MPA 

Other 

Unsure 

Not reported 

17. Concomitant immuno. therapy 

Cyclosporine 

Tacrolimus 

Methylprednisolone 

Prednisone 

Corticosteroids 

Other1 

None 

Unsure 

Not reported 

 
B-7 

18. Method of MPA measurement (provide relevant details in text box) 

Pre-dose concentration 

Post dose time points 

Maximum concentration 

Full AUC 

Abbreviated AUC 

Other 

Unsure 

Not reported 

 

19. Frequency of MPA monitoring 

 

20. Assay used to quantitate MPA 

HPLC 

EMIT 

LC-MS 

Other1 

Unsure 

Not reported 

21. Health outcome which is related to data for MPA blood levels 

1. Describe 

2. Describe 

3. Describe 

4. Describe 

5. Describe 

6. Describe 

7. Others 

 

22. Length of follow-up 

23. Is this paper a companion to another paper? 

Yes (give RefID # if known) 

Maybe (give RefID # if known)

No 
B-8 

24. Does this study compare outcomes for subjects 

 i) with planned dose adjustments based on MPA blood levels 

versus 

ii) subjects taking MPA without changes based on blood levels 
B-9 

Level 13 – Quality 

1. What study design is used? 

Randomized controlled trial 

Non-randomized controlled trial 

Observational (cohort, case-control, case series)

Other (describe) 

ANSWER FOR CONTROLLED TRIALS ONLY

 YES NO Referred to 

other publication

2. Did the authors describe a method of randomization? Clear

3. Did the authors describe a method of allocation 

concealment?

Clear

 

4. Did the authors report a baseline comparison of 

groups? Clear

5. Were there differences between groups at baseline? Clear

 

6. Did the study use an intent-to-treat analysis (or did the 

reported results permit the calculation of intent-to-treat 

results)? Clear

7. Did the authors clearly describe the methods used to 

measure MPA?

Clear

 

8. Did the authors clearly define the outcomes related to 

monitoring MPA?

Clear

9. Were subjects blinded? Clear

10. Were persons measuring MPA blinded as to 

outcome? Clear

11. Were persons assessing outcomes blinded as to 

measures of MPA? Clear

12. Was there a differential loss to follow-up between 

groups?

Clear
B-10 

ANSWER FOR OBSERVATIONAL STUDIES ONLY (COHORT, CASECONTROL, CASE SERIES)

13. Was the sample size large enough to detect statistically significant differences in primary 

outcomes?

Yes 

No 

14. Was the sample size large enough to detect statistically significant differences in secondary 

outcomes? 

Yes 

No 

Not applicable 

15. How were study participants selected from the study population? 

Consecutively 

Convenience 

Other (describe) 

Referred to other publication 

Not reported 

16. Did the authors report a baseline comparison of study groups (exposure groups for cohort 

studies; outcome groups for case-control studies)? 

Yes 

No 

Referred to other publication 

Not applicable, study was a case series

17. Were there difference between groups at baseline? 

Yes 

No 

Referred to other publication 

Not applicable 

Not reported 
B-11 

18. Did the authors clearly describe the methods used to measure MPA? 

Yes 

No 

Referred to other publication 

19. Did the authors clearly define the outcomes related to monitoring MPA? 

Yes 

No 

Referred to other publication 

20. Were subjects blinded? 

Yes 

No 

Not reported 

21. Were persons measuring MPA blinded as to outcome? 

Yes 

No 

Not reported 

22. Were persons assessing outcomes blinded as to measures of MPA? 

Yes 

No 

Not reported 

23. Was there a differential loss to follow-up between groups? 

Yes 

No 

Not reported 

Not applicable 

24. Did the authors control for confounding?

Yes 

No 

Not applicable 
B-12 

Guide to Full Text Screening for MPA Monitoring Review

Question 1. Is this report published in English? 

• If the abstract only is English, mark as ‘NO’ 

Question 2. Is the publication a peer reviewed full report of an RCT, cohort 

study, case-series or case-control study (is not a case report, review, overview, 

discussion piece, conference report/proceeding, abstract, editorial, or letter to the 

editor)? 

• These are study designs as defined by the Cochrane Collaboration, “The 

Cochrane Reviewers’ Handbook Glossary” 

http://www.cochrane.org/resources/handbook/glossary.pdf

Question 3. Are subjects, humans with solid organ transplants? 

• There is no age limitation for the subjects. 

• There is no concomitant disorder limitation for the subjects. 

• Solid organ transplants include: heart, intestines, kidney, liver, lung, 

pancreas. 

• Islet cell transplants or any hematopoetic cell transplants are not 

considered solid organ transplants. 

Question 4. Is any form of MPA measured in the blood? 

• Metabolites that may be measured include: 

 MPA 

 mycophenolic acid 

 (UGTs). 7-O-MPA-glucuronide (MPAG) 

 MPA glucuronide (MPAG) 

 MPAG 

 MPA Acyl glucuronide (AcMPAG) 

• Form: free or total MPA can be measured by: 

 Albumin measurement 

 Pharmacogenomics and metabolite levels 

 HPLC 

 HPLC-MS 

 EMIT 

 Other 

• Method of MPA measured can include: 

 Full area under the curve (AUC) 
B-13 

 Trough levels 

 2-hour post dose levels 

 Other 

Question 5. Is any form of MPA monitored in the blood (measured with the 

intent of using the result for any action, based on the MPA blood level) ? 

• Monitoring refers to measuring blood levels with the intention for any 

action based on the blood level 

Question 6. Are MPA blood levels associated with any clinical health outcome? 

• Clinical health outcomes include any indication of transplant rejection or 

adverse events 

• There is a list provided for example only. There are no clinical outcomes 

that should not be included at this level 

• Examples of clinical health outcomes are: death, re-transplantation, 

hepatitis, malignancy, rejection, hemodialysis, cardiac arrest or MI, 

bleeding, hospital stay, hospital admission, infection...... 

• Let in any health outcome and the clinician responsible for that section will 

decide if it is pertinent to the review question
B-14 

Structured Format for Collecting Referee Comments

We are pleased that you have agreed to review this interim report and thank you 

in advance for your time. We greatly value your feedback and have provided a 

series of questions to collect your comments. 

Please note that we are constrained to the format and style of the report as 

prescribed by AHRQ publication guidelines. However, within this framework, we 

also ask that you comment on the style and format of the report for purposes of 

disseminating these findings. 

Thank you again for reviewing this report. 

GLOBAL IMPRESSIONS 

• Provide your comments on the strengths of the report or those components 

you valued most. 

• Provide your comments on those general areas where this report can be 

strengthened. 

SPECIFIC COMPONENTS OF THE SYSTEMATIC REVIEW 

Structured Abstract 

• Was it clear? 

Executive Summary 

• Was it clear? 

• Were the clinically meaningful messages featured? 

Study Identification 

• Was the literature search thorough and complete? 

Study Selection 

• Are appropriate inclusion and exclusion criteria used to select articles? 

• Are selection criteria applied in a manner that limits bias? (e.g. publication 

bias) 

Appraisal of Studies 

• Are the salient points in the literature on this topic adequately summarized 

and discussed? 

• Are important parameters (e.g., setting, study population, study design) that 

could affect study results systematically addressed in text or tables? 

• Is there any missing information that should be included in the text or tables? 
B-15 

Discussion 

• Are limitations and inconsistencies of studies stated? 

• Are limitations of the review process stated? 

• Are implications for research discussed 

• Are implications for practice discussed? 

Conclusions 

• Are conclusions supported by the data reviewed? 

• Is evidence appropriately interpreted as indirect or inconclusive (no evidence 

of effect)? 

• Are the recommendations valid, given the available evidence? 

• Is a summary of pertinent findings provided? 

OPEN COMMENTS 

If there any other comments you would like to add, please do so here. 
C-1

Appendix C. Evidence Tables 

 

Evidence Table 1. General information for all included studies 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Armstrong 

Year: 

2001 

Country: 

Germany 

Aim: 

Compare the clinical 

utility of the EMIT 

assay with HPLC for 

discriminating acute 

rejection in pediatric 

renal transplant 

recipients 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

40 

Analyzed: 

40 

Population: 

Pediatric renal tx; 

9 patients: > 1 

acute rejection 

episode 

31 patients: no 

rejection episode 

Organ

transplanted: 

Kidney (Renal) 

Age: Inclusion 

requirement 

pediatric 

Mean NR 

% Male: NR 

Weight: NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 600 mg/m2

BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Methylpred. 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

 Co, AUC(0-12h), 

Cmax

Frequency of 

MPA measure: 

day 7, day 21 

Assay used: 

HPLC 

EMIT 

Health 

outcome: 

acute 

rejection 

Length of 

followup: 

70d 

Abbreviations: AcMPAG=Acyl Glucuronide metabolite of mycophenolic acid; AE=adverse effects; AE/R=adverse 

effects/rejection; AR=acute rejection; AUC=area-under-the-concentration-time curve; ATG= anti-thymocyte globulin; ATS=antithymocyte serum; AZA=azathioprine; BID=twice daily; BSA=body surface area; C0=predose trough blood concentration; 

CC=concentration controlled; CL/F=total body clearance; Cmax=maximum blood or plasma concentration; Cmin=minimum blood 

or plasma concentration; CMV=cytomegalovirus; CNI=calcineurin inhibitors; CsA=cyclosporin A; d=days; DGF=delayed graft 

function; Elisa=Enzyme-Linked ImmunoSorbent Assay; E-MPS=enteric-coated mycophenolate sodium; EMIT=enzyme-multiplied 

immunoassay technique; FD=fixed dose; fMPA=free mycophenolic acid; GFR=glomerular filtration rate; GI=gastrointestinal; 

H=high; Hb=haemoglobin; HCV=hepatitis C virus; HPLC=high-performance liquid chromatography I=intermediate; 

IMPDH=Iosine 5'-monophosphate dehydrogenase; IRF=impaired renal function; L=low; LSS=limited sampling strategy; MEIA 

II= microparticle enzyme immunoassay; Methylpred.=methylprednisolone; MMF=mycophenolate mofetil; m=months; 

MPA=mycophenolic acid; MPAG=mycophenolic acid glucuronide; LC-MS=liquid chromatography-mass spectrophotometry; 

NR=not reported; OKT3= muromonab-CD3; PK=pharmacokinetic; PSL=prednisolone; RBC=red blood cells; RCT=randomized 

controlled trial; ROC=receiver operating characteristic; RR=relative risk; SGOT=serum glutamic oxaloacetic transaminase; 

SGPT=Serum glutamic pyruvic transaminase; SIR=sirolimus; Tac=tacrolimus; TB=tuberculosis; TDM=therapeutic drug 

monitoring; Tmax=mean time to maximum concentration; tx=transplant; UV=ultraviolet; WBC=white blood cells; y=years 
C-2

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Atcheson 

Year: 

2004 

Country: 

Australia 

Aim: 

To investigate PK of 

MPA 

Comparison of 

monitored patients 

with others: No 

Study design: 

Prospective Cohort 

Entered into study: 

42 

Analyzed: 

42 

Population: 

Caucasian 98% 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 44.3 +/- 

13.1y 

% Male: 57 

Weight: 

Mean 72.9 +/- 

14.8 kg 

BMI 25.3 +/- 3.9 

kg/m2

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1g BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

n=32 

Tacrolimus n=10 

Simulect 

Diltiazem 

Prednisolone 

 

Form 

measured: 

MPA 

fMPA 

Method of 

measurement: 

AUC(0-6h)

Co 

Frequency of 

MPA measure: 

day 5 after 

transplantation 

Assay used: 

HPLC UV and 

MS-MS 

Health 

outcome: 

acute 

rejection 

GI 

anemia 

thrombocytopenia 

leucopenia 

Length of 

followup: 

1m 

Author: 

Barbari 

Year: 

2005b 

Country: 

Lebanon 

Aim: 

To determine MPA 

trough level 

correlation with 

outcomes 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case control 

Entered into study: 

30 

Analyzed: 

NR 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 39y 

Range 20–67y 

% Male: 63.3 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g 2 times 

a day range 1 - 

2.5 g/day 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

Frequency of 

MPA measure: 

NR 

Assay used: 

monoclonal 

antibody based 

ELISA kit 

Health 

outcome: 

acute 

rejection 

lymphocyte 

count 

Length of 

followup: 

NR 
C-3

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Barbari 

Year: 

2005a 

Country: 

Lebanon 

Aim: 

To assess 

realtionship between 

clinical outcome, 

lymphocyte count 

and cyclosporine 

lymphocyte max 

level 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case control 

Entered into study: 

Condition 1, graft 

dysfunctions: 12 

Condition 2, no 

events: 23 

Analyzed: 

NR 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: 

NR 

% Male: 

NR 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 2 g/day 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Form 

measured: 

NR 

Method of 

measurement: 

NR 

Frequency of 

MPA measure: 

NR 

Assay used: 

NR 

Health 

outcome: 

acute 

rejection 

Length of 

followup: 

NR 

Author: 

Behrend 

Year: 

1997 

Country: 

Germany 

Aim: 

MPA and MPAG 

trough levels after 

renal transplantation 

Comparison of 

monitored patients 

with others: No 

Study design: 

RCT 

Entered into study: 

57 

Analyzed: 

48 

Population: 

followup to a 

previously 

reported RCT; 

Organ

transplanted: 

Kidney (Renal) 

Age: 

NR 

% Male: 

NR 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 2 g/day or 

3 g/day; dose per 

body weight was 

22 to 54 mg/kg; 

mean 83 mg/kg ±

8.4 body weight 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Corticosteroids 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

 trough levels 

Frequency of 

MPA measure: 

samples from 

patients varied 

from 4-32 

Assay used: 

HPLC 

Health 

outcome: 

graft 

function 

adverse 

events 

infections 

acute 

rejection 

Length of 

followup: 

≥1y 
C-4

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Bilbao 

Year: 

2006 

Country: 

Spain 

Aim: 

Immunosuppression 

based on MMF in 

stable liver 

transplanted 

patients. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

56 

Analyzed: 

56 

Population: 

Stable liver 

transplant 

patients 

Organ

transplanted: 

Liver 

Age: 

Mean 59 +/ - 6y 

% Male: 61% 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) MMF 

Dose: Initial dose 

of 500 mg/12h; 

reaching dose of 

1 g each 12h for 2 

weeks. 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

adjusted to 

tolerability and 

side effects 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Form 

measured: 

MMF only 

mentioned but 

meant MPA 

Method of 

measurement: 

 trough levels 

Frequency of 

MPA measure: 

Every 3 months 

for the first year, 

every 6 months 

until the 4th year 

then yearly until 

year 6. 

Assay used: 

NR 

Health 

outcome: 

acute 

transplant 

rejection 

death 

progression 

of renal 

dysfunction 

progression 

of HCV 

recurrence 

mild 

diarrhea 

leucopenia 

de novo 

tumour 

Length of 

followup: 

mean 39 ±

20m; range 

3 to 72m. 

Author: 

Borrows 

Year: 

2006 

Country: 

UK 

Aim: 

TDM of MPA 

associations with 

toxicity and 

rejections 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

121 

Analyzed: 

121 

Population: 

Caucasian 55% 

South Asian 23% 

Afro-Carib 18% 

Other 4% 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 46 +/- 9y 

Range 37–55y 

% Male: 58 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 750 mg 

BID 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators only 

Concomitant

medications: 

Tacrolimus 

Methylpred. 

Prednisone 

Corticosteroids 

Ganciclovir (for 

3m) 

Co-trimoxazole 

(for 6m) 

Isoniazid and 

pyridoxine (in 

Indo-Asians and 

previous TB) 

Basiliximab or 

Daclizumab (in 79 

patients) 

Form 

measured: 

MPA 

Method of 

measurement: 

 trough levels 

Frequency of 

MPA measure: 

day 7, month 1, 

3, 6, 12 

Assay used: 

EMIT 

Health 

outcome: 

acute 

rejection 

white blod 

cell count 

leucopenia 

thrombocyt

openia 

bacteria/vira

l infection 

heamoglobi

n/anemia 

Length of 

followup: 

minimum of 

12m 

median 

25m 

range 13-

38m 
C-5

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Borrows 

Year: 

2005 

Country: 

UK 

Aim: 

To understand the 

determinants of MPA 

levels and thus aid 

TDM of MMF 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

117 

Analyzed: 

115 after 6m 

Population: 

White 55.6% 

Indo-Asian 23.1 

Afro-Carib 17.9% 

Other 3.4 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 46 +/- 9y 

Range 37-55y 

% Male: 58.1 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 250-3000 

mg/day 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Tacrolimus 

Methylpred. 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

Frequency of 

MPA measure: 

week 1, 2, 3, 4, 

month 2-3, 4-6, 

7-12, >12 

Assay used: 

EMIT 

Health 

outcome: 

diarrhea 

Length of 

followup: 

30 m 

median 

19m 

range 6 – 

30m 

Author: 

Braun 

Year: 

1998 

Country: 

Germany 

Aim: 

Assess the 

relationship between 

therapeutic drug 

monitoring and 

clinical course in 

kidney and liver 

recipients. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Prospective Cohort 

Entered into study: 

28 

Analyzed: 

28 

Population: 

patients receiving 

a tacrolimus 

based 

immunosuppressi

ve regimen. 

Organ

transplanted: 

Kidney (Renal) 

Liver 

Age: 

NR 

% Male: 

NR 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 30-40 

mg/kg/day 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Tacrolimus 

Form 

measured: 

MPA 

Method of 

measurement: 

 trough 

Frequency of 

MPA measure: 

Not reported 

Assay used: 

HPLC 

MEIA II 

Health 

outcome: 

liver 

rejection 

dirrhea 

CMV 

infection 

G.I. 

symptoms 

Length of 

followup: 

median 

280d 

range 

19-585d 
C-6

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Brunet 

Year: 

2006 

Country: 

Spain 

Aim: 

To determine 

whether MPA 

monitoring is 

advisable in liver 

transplant patients 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

15 

Analyzed: 

day 6 n=13, 

day 10 n=13, 

day 16 n=14, 

month 3 n=10, 

month 6 n=13 

Population: 

NR 

Organ

transplanted: 

Liver 

Age: 

Range 29–66y 

% Male: 60 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g twice a 

day 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Tacrolimus 

Methylpred. 

Daclizumab 

Form 

measured: 

MPA 

Method of 

measurement: 

Co, Cmax, 

AUC0-12

Frequency of 

MPA measure: 

day 6, 10, 16 

month 3, 6 

Assay used: 

HPLC 

Health 

outcome: 

diarrhea 

nausea 

Length of 

followup: 

6m 

Author: 

Brunet 

Year: 2000 

Country: 

Spain 

Aim: Compare the 

MPA 

pharmacokinetic 

profile and its 

pharmacodynamic 

effect on petients 

recieving either 

standard (2 g) or low 

(1.5 g or 1 g) MMF 

doses, in order to 

evaluate the 

therapeutic efficiacy 

of such low doses in 

inhibiting IMPDH 

activity 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case control 

Entered into study: 

27 

Analyzed: 

27 

Population: 

Stable renal tx 

recipients 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 42.5 +/- 

13.6 y 

Range 18-65y 

% Male: 

NR 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g, .075 g, 

and 0.5 g 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Prednisone 

CsA 

Form 

measured: 

MPA 

Method of 

measurement: 

Co, Cmax, 

AUC0-12

Frequency of 

MPA measure: 

NR 

Assay used: 

HPLC 

Health 

outcome: 

IMPDH 

activity

Length of 

followup: 

38.5m 

(6-166m) 
C-7

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Brusa 

Year: 

2000 

Country: 

Italy 

Aim: 

Ascertain any 

correlation between 

MPA plasma 

concentrations in 

patients receiving an 

oral daily dose of the 

drug after an allograft renal 

transplantation, and 

a number of 

variables, such as 

time-course, drug 

dosage (fixed or per 

body weight), 

frequency 

Comparison of 

monitored patients 

with others: No 

Study design: 

Prospective Cohort 

Entered into study: 

23 

Analyzed: 

23 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range: 

18 patients 13-

58y 

5 patients 35-56y 

% Male: 83 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 250 to 

1000 mg/day BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Corticosteroids 

Form 

measured: 

trough 

Method of 

measurement: 

trough 

Frequency of 

MPA measure: 

once, 

immediately 

post tx OR in 

advanced 

therapy 

Assay used: 

HPLC 

Health 

outcome: 

serious side 

effects 

interstitial 

rejection 

Length of 

followup: 

>12m 

Author: 

Bunchman 

Year: 

2001 

Country: 

USA 

Aim: 

To evaluate the 

safety, tolerability 

and 

pharmacokinetics of 

MMF suspension in 

pediatric renal 

recipients 

Comparison of 

monitored patients 

with others: No 

Study design: 

Prospective Cohort 

Entered into study: 

100 

Analyzed: 

72 

Population: 

64 patients were 

from North 

America, 4 from 

Australia and 32 

from Europe 

Organ

transplanted: 

Kidney (Renal) 

Age: Inclusion 

requirement 3m - 

18y 

% Male: 68 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) oral 

suspension 

Dose: 600 mg/m2 

BID up to 1 g BID 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 49% of 

patients 

experienced 

adverse events 

that resulted in 

MMF dose 

reduction or 

interuption 

Concomitant

medications: 

Cyclosporine 

Corticosteroids 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

AUC(0-12h)

Frequency of 

MPA measure: 

on day 7 and at 

3, 9, 24 and 36 

m 

Assay used: 

LC-MS liquid 

chromatography 

Health 

outcome: 

acute 

rejection 

leucopenia 

diarrhea 

sepsis 

abdominal 

pain 

fever 

Length of 

followup: 

36m 
C-8

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Cantin 

Year: 

2002 

Country: 

USA 

Aim: 

To determine clinical 

relevance of MPA 

monitoring and 

examine its 

correlation with 

calcineurin 

antagonists and 

acute rejection 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

26 

Analyzed: 

22 

Population: 

NR 

Organ

transplanted: 

Heart (Cardiac) 

Age: 

Mean 54.4 +/- 14y 

Range 22–72y 

% Male: 73 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: Tac group: 

1810 mg/day +/- 

817, CsA group: 

2447 +/- 896 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Corticosteroids 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

trough levels 

Frequency of 

MPA measure: 

NR 

Assay used: 

HPLC 

Health 

outcome: 

asymptomat

ic rejection 

Length of 

followup: 

1y 

Author: 

Cattaneo 

Year: 

2001 

Country: 

Italy 

Aim: 

To optimize MMF 

dosing by monitoring 

MPA PK 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

46 

Analyzed: 

46 

Population: 

adult renal tx 

patients 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean AUC >40 

ug.ml h: 31.9 +/- 

9.0y 

Mean AUC <40 

ug.ml h: 39 +/- 

12.4y 

Range 19-61y 

% Male: 63 

Weight: 

Mean AUC >40 

ug.ml h: 61.7 +/- 

11.3kg, 

Mean AUC <40 

ug.ml h: 67 +/- 

12.9kg 

Range 44-97kg 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 2 g/day 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Cyclosporine 

Prednisone 

CsA Neoral 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

Co, AUC0-12 (as 

predicted by 

LSS AUC0-2) 

Frequency of 

MPA measure: 

NR 

Assay used: 

HPLC 

Health 

outcome: 

creatinine 

anemia 

Length of 

followup: 

9m 
C-9

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Deierhoi 

Year: 

1993 

Country: 

USA 

Aim: 

Phase I trial: to study 

dose ranging and 

side effects Rescue 

trial: to study MMF 

as rescue therapy in 

acute rejection 

Comparison of 

monitored patients 

with others: No 

Study design: 

Prospective Cohort 

Entered into study: 

Condition 1: 

21 phase I 

Condition 2: 

100 quadruple 

therapy 

Condition 3: 

26rescue therapy 

Condition 4: 

39 steroid rescue 

Analyzed: 

Condition 1: 

18 phase I 

Condition 2: 

NR quad therapy 

Condition 3: 

25 rescue therapy 

Condition 4: 

NR steroid rescue 

Population: 

55.9% black, 2% 

other, 43% white 

Organ

transplanted: 

Kidney (Renal) 

Age: Inclusion 

requirement 

phase I: older 

than 18, rescue: 

older than 16 

% Male: 54.8 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: phase I: 

1500 - 3000 

mg/day rescue: 

2000 mg/day and 

3000-3500 

mg/day if no 

response in first 

week to 2000 mg 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators side 

effects - phase I: 

diarrhea, rescue: 

diarrhea and 

nausea 

Concomitant

medications: 

Cyclosporine 

phase I and 

rescue 

 Methylpred. 

phase I 

Prednisone 

rescue 

Corticosteroidsph

ase I phase I and 

rescue: 

Minnesota 

antilymphocyte 

globulin(MALG) 

rescue: 

azathioprine 

Form 

measured: 

MPA 

Method of 

measurement: 

 trough levels, 

peak 

concentration 

Frequency of 

MPA measure: 

Day 1, 7, 14, 20 

Assay used: 

HPLC 

Health 

outcome: 

diarrhea - 

phase 1 

and rescue 

nausea - 

phase 1 

and rescue 

elevated 

liver 

enzymes - 

phase 1 

Length of 

followup: 

phase I trial: 

mean 26m 

range 22 - 

28m 

rescue: 

mean 20m 

range 16 - 

24m 
C-10

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

DeNofrio 

Year: 

2000 

Country: 

USA 

Aim: 

To determine the 

clinical significance 

of MPA 

concentrations 

following orthotopic 

heart transplantation 

(OHT) 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

38 

Analyzed: 

38 

Population: 

Tx patients with 

surveillance 

biopsy 

Organ

transplanted: 

Heart (Cardiac) 

Age: 

Mean 53 +/- 10y 

% Male: 82 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1g BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Form 

measured: 

MPA 

fMPA 

Method of 

measurement: 

Co, Cmax, 

AUC0-12 (as 

predicted by 

LSS Co, C20, C40, 

C75, C120) 

Frequency of 

MPA measure: 

once on MMF 

Assay used: 

HPLC 

Health 

outcome: 

rejection 

cardiac 

allograft 

Length of 

followup: 

310 ±278d 

Author: 

Dipchand 

Year: 

2001 

Country: 

Canada 

Aim: 

Review our 

experience with 

MMF dosing and the 

role of MPA levels 

for therapeutic drug 

monitoring in a 

population of 

pediatric heart 

transplant recipients 

Comparison of 

monitored patients 

with others: No 

Study design: 

Retrospective Cohort 

Entered into study: 

44 

Analyzed: 

44 

Population: 

Pediatric heart tx 

Organ

transplanted: 

Heart (Cardiac) 

Age: 

Range 29d-23.5y 

Median 6.3y 

% Male: 61 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: various: 

15-159 mg/kg 

Prospective

dose adjustment

planned: required 

based on clinical 

indicators 

Concomitant

medications: 

Cyclosporine (A 

or neural) 

Tacrolimus 

Corticosteroids 

azathiaprine 

ATG 

OKT3 

ATS 

Form 

measured: 

MPA 

Method of 

measurement: 

Trough 

Frequency of 

MPA measure: 

various: 1-7 

levels 

Assay used: 

EMIT 

Health 

outcome: 

rejection 

Length of 

followup: 

8w 
C-11

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Filler 

Year: 

2000 

Country: 

Germany 

Aim: 

Replacing Aza with 

MMF in long term 

renal transplant 

recipients with 

evidence of CsA 

toxicity, thus allowing 

a safer reduction of 

CyA without an 

increased risk of 

rejection. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

18 

Analyzed: 

18 

Population: 

Pediatric and 

adolescent renal 

tx recipients with 

chronic CyA 

toxicity 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 17.2 y + 4.3 

SDy 

% Male: 50 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 600 mg/m2 

BID 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Cyclosporine 

Steroids 

Azathioprine(13 

patients but 

weaned off in 2) 

ATG-induction (5 

patients) 

Tacrolimus (1 

patient due to 

resistance but 

weaned off soon 

after due to side 

effects) 

Form 

measured: 

MPA 

Method of 

measurement: 

Co

AUC(0-12)

Frequency of 

MPA measure: 

all = 21 days +/- 

17; 1 to 4 

profiles 

Assay used: 

HPLC 

EMIT 

Health 

outcome: 

leucopenia 

thrombocyt

openia 

diarrhea 

Length of 

followup: 

Mean 6.2 ±

2.7y 

Range 2.3-

11.8y 
C-12

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Filler 

Year: 

1998 

Country: 

Germany 

Aim: 

MMF with Tac for 

steroid-resistant 

vascular rejection in 

pediatric renal 

allografts 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

7 

Analyzed: 

7 

Population: 

Adolescent renal 

transplant 

recipients having 

an acute rejection 

episode. 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 15.8 +/- 

1.6y 

Range 13 - 18y 

% Male: 29% 

Weight: 

Not reported 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) MMF 

Dose: 600 mg/m2 

BID reduced to 

320 mg/m2 /day 

over 7 wks 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels trough 

concentrations 

were used to 

adjust MMF 

doses 

Concomitant

medications: 

Tacrolimus 

Methylpred. 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

Co 

AUC0-12

Frequency of 

MPA measure: 

Repetetive 

blood sampling 

from before 

dose and then 9 

more times after 

dosage in the 

next 12 hours. 

Drug monitoring 

was performed 

by the 

estimation of 

trough 

concentration 

and 

pharmacokinetic 

profile between 

days 10 and 18. 

Assay used: 

HPLC 

Health 

outcome: 

renal graft 

losses 

severe 

diarrhea 

Length of 

followup: 

range 49-

503d, 

mean 282d 

Author: 

Flechner 

Year: 

2005 

Country: 

USA 

Aim: 

To determine 

efficacy & side 

effects of low dose (1 

g) MMF in a CNI 

drug avoidance 

regimen including 

sirolimus/steroids 

Comparison of 

monitored patients 

with others: Yes 

versus clinically 

driven dose changes 

Study design: 

Prospective Cohort 

Entered into study: 

Condition 1 160 

Condition 2 100 

Analyzed: 

Condition 1 160 

Condition 2 100 

Population: 

White 79%, Black 

18%, Others 3% 

Organ

transplanted: 

Kidney (Renal) 

Age: Mean 48.5 

% Male: 66.5 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1g BID 

(n=160) and 500 

mg BID (n=100) 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels 

Concomitant

medications: 

Methylpred. 

 Basiliximab 

Sirolimus 

Diltiazem 

Thymoglobulin 

Form 

measured: 

MPA 

Method of 

measurement: 

Co level 

Frequency of 

MPA measure: 

At 2wks, 1m , 

3m and 6m 

Assay used: 

HPLC 

Health 

outcome: 

Acute 

rejections 

CMV 

infections 

Polyoma 

(BK) viral 

infections 

GI 

complaints 

Nausea/ 

vomitting/ 

dyspepsia, 

abdomenal 

pains, and 

diarrhea. 

Length of 

followup: 

6m 
C-13

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Gajarski 

Year: 

2004 

Country: 

USA 

Aim: 

To determine 

correlation between 

MMF dose and MPA 

level and impact on 

rejection among 

young cardiac 

receipients 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

26 

Analyzed: 

26 

Population: 

16 children, 10 

adults 

Organ

transplanted: 

Heart (Cardiac) 

Age: 

Mean 15.4 +/- 

9.5y 

Range 1 m-33y 

% Male: 

NR 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: average 

1206.8 +/- 301.9 

mg/m2 and 37.9 

+/- 12.5 mg/kg 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

Co

Frequency of 

MPA measure: 

NR 

Assay used: 

HPLC 

Health 

outcome: 

biopsy 

grades 

Length of 

followup: 

NA 

Author: 

GonzalesRoncero 

Year: 

2005 

Country: 

USA 

Aim: 

To determine the 

effects of renal 

insufficiency on PK 

of MMF 

Comparison of 

monitored patients 

with others: No 

Study design: 

Prospective Cohort 

Entered into study: 

Condition 1 10 

Condition 2 10 

control 

Analyzed: 

Condition 1 10 

Condition 2 10 

control 

Population: 

Cadaveric donor 

renal tx patients 

Organ

transplanted: 

Kidney (Renal) 

Age: 

NR 

% Male: 

NR 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: group I: 

185 +/- 0.2 g/day 

group II: 1.7 +/- 

0.5 g/day 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Form 

measured: 

MPA 

MPAG 

free MPA 

Method of 

measurement: 

 AUC(0-12h)

Frequency of 

MPA measure: 

0, 20, 40, 75 

minutes 1, 2, 3, 

4, 6, 8, 10, 12 

hours after MMF 

dose 

Assay used: 

HPLC/UV 

Health 

outcome: 

renal 

insufficiency 

Length of 

followup: 

>1y 
C-14

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Grasser 

Year: 

2001 

Country: 

Austria 

Aim: 

Present a 

nonblinded, 

nonrandomized longterm followup study 

to evaluate MPA 

trough level 

measurement for the 

quidance of MMF 

rejection prophylaxis 

after Liver TX. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

11 

Analyzed: 

10 

Population: 

adult liver tx 

recipients 

Organ

transplanted: 

Liver 

Age: 

Mean 56y 

Range 27-70y 

% Male: 73 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: NR: Target 

concentration = 

1ug/mL 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels 

Concomitant

medications: 

 Methylpred. 

Orednisone 

horse ATG 

Apredisolone 

Form 

measured: 

MPA 

Method of 

measurement: 

 trough 

Frequency of 

MPA measure: 

daily for 2 

weeks, then 

every other 

week 

Assay used: 

EMIT 

Health 

outcome: 

SGOT 

SGPT 

Bilirubin 

Leucopenia 

Length of 

followup: 

6m 

Author: 

Hale 

Year: 

1998 

Country: 

Netherlands, 

Belgium 

Aim: 

Confirm the 

observed 

pharmacokineticpharmacodynamic 

relationship by 

studying the 

relationship between 

MPA PF and the 

likelihood of rejection 

Comparison of 

monitored patients 

with others: Three 

target MPA AUC 

values compared 

Study design: 

RCT 

Entered into study: 

Condition 1 L: 51 

Condition 2 I: 47 

Condition 3 H: 52 

Analyzed: 

Condition 1 L:29 

Condition 2 I: 28 

Condition 3 H: 20 

Population: 

Recipients of 1st 

or 2nd kidney; 

140 of 150 were 

caucasian 

Organ

transplanted: 

Kidney (Renal) 

Age: Inclusion 

requirement 

> 18y 

Range 

L: 47.8 +/- 11.5; 

I: 46.9 +/- 13.8; 

H: 50.6 +/- 10.5 

% Male: 

L: 58.8; 

I: 63.8; 

H: 59.6 

Weight: 

L: 69.8 +/- 12.5 

I: 65.9 +/- 13/1 

H: 67.4 +/- 11.3 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: L: 0.45 g 

BID then adj I: 

0.95 g BID then 

adj H: 1.7 g BID 

then adj 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels 

Concomitant

medications: 

Cyclosporine 

Corticosteroids 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

Cmax 

AUC0-12

Frequency of 

MPA measure: 

day 3,7,11,21,28 

week 8,12,16,20 

Assay used: 

HPLC 

Health 

outcome: 

Acute 

rejection 

adverse 

events 

(vomit, 

abdominal 

pain, 

diarrhea, 

leukopenia, 

pneumonia) 

Length of 

followup: 

6m 
C-15

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Hazzan 

Year: 

2005 

Country: 

France 

Aim: 

To compare 

incidence of acute 

rejection after 

withdrawal from CsA 

or MMF 

Comparison of 

monitored patients 

with others: No 

Study design: 

RCT 

Entered into study: 

CsA group: 54 

MMF group: 54 

Analyzed: 

CsA group: 54 

MMF group: 54 

Population: 

BMI CsA group 

23.3 +/- 3.9, MMF 

group 24.0 +/- 

11.2 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean CsA group 

42.5 +/- 12.1 

MMF group 45.1 

+/- 11.2 

% Male: 63 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 

CsA group MMF 

dose = 1.93 +/- 

0.2 then 

withdrawn to 0, 

MMF group MMF 

dose = 1.99 +/- 

0.1 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

AUC(0-12)

Co

Frequency of 

MPA measure: 

Once at 3 m 

Assay used: 

Enzyme 

Health 

outcome: 

acute 

rejection 

Length of 

followup: 

1y 

Author: 

Heller 

Year: 

2007 

Country: 

Germany 

Aim: 

Study the relation of 

plasma 

concentrations of 

AcMPAG and MPAG 

with the incidence of 

diarrhea 

Comparison of 

monitored patients 

with others: 

No 

Study design: 

Prospective Cohort 

Entered into study: 

290 

Analyzed: 

290 

Population: 

Organ

transplanted: 

Kidney 

Age: 

53.4y 

% Male: 

62 

Weight: 

NR 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 

Fixed Dose group: 

1 g BID, Controlled 

Concentration 

group: target 

concentration of 

30-60 mg*h/L 

Prospective dose

adjustment

planned: 

Yes, based on 

MPA (or 

metabolite) blood 

levels 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Form 

measured: 

MPA, MPAG, 

AcMPAG 

Method of 

measurement: 

Abbreviated 

AUC (0, 30m, 

2h) 

Frequency of 

MPA 

measure: 

Day 3, 10, 

week 4, 

months 3, 6 

and 12 

Assay used: 

HPLC initially 

then later, LCMS 

Health 

outcome: 

Diarrhea 

Length of 

followup: 

12m 
C-16

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Hesse 

Year: 

2001 

Country: 

Netherlands 

Aim: 

To evaluate the need 

for routine monitoring 

of MPA trough 

plasma levels to 

prevent acute 

rejection in heart 

transplant recipients 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

20 

Analyzed: 

20 

Population: 

NR 

Organ

transplanted: 

Heart (Cardiac) 

Age: 

NR 

% Male: 

NR 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1500 mg 

BID + dose 

reductions on 

clinical symptoms 

Prospective dose

adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Tacrolimus 

Prednisone 

CsA 

Form 

measured: 

MPA 

Method of 

measurement: 

Co

Frequency of 

MPA 

measure: at 

biopsy 

Assay used: 

EMIT 

Health 

outcome: 

acute 

rejection 

biopsy 

score 

Length of 

followup: 

Mean 

10.1m 

Author: 

Hubner 

Year: 

2000 

Country: 

Germany 

Aim: 

To determine the 

relationship between 

MMF side effects 

and MPA trough 

levels in renal 

transplant patients 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

30 

Analyzed: 

30 

Population: 

adult renal tx 

recipient 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 45y 

% Male: 66.7 

Weight: 

Mean for entire 

population mean 

body weight 73 kg 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1.0 g twice a 

day 

Prospective dose

adjustment

planned: Yes - 

based on clinical 

indicators adverse 

events 

Concomitant

medications: 

Cyclosporine 

Methylpred. 

Form 

measured: 

MPA 

Method of 

measurement: 

Predose 

concentration 

Frequency of 

MPA 

measure: 3-4 

times a wk for 

the first month, 

once a wk 

during the 

second month 

and once a 

month 

thereafter 

Assay used: 

EMIT 

Health 

outcome: 

acute 

rejection 

leucocyte 

count 

other 

adverse 

reactions 

(cytomegalo

virus 

infection, 

pneumonia, 

urinary tract 

infection, 

herpes 

zoster, 

infected 

hematoma, 

pancreatitis, 

leucopenia) 

Length of 

followup: 

NR 
C-17

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Johnson 

Year: 

1999 

Country: 

Australia 

Aim: 

To determine 

whether MPA 

kinetics vary after 

renal trasplantation 

and to examine the 

potenial role of 

enterohepatic 

recirculation. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

10 

Analyzed: 

10 

Population: 

consecutive 

kidney transplant 

recipients 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 41.7 +/- 

5.0y 

% Male: 60 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g BID 

Prospective dose

adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Methylpred. 

ranitidine 

sulfamethoxazole/tr

imethoprim 

iron supplements 

amphotericin 

lozenges 

diltiazem 

calcitrol 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

AUC(0-12H)

tmax 

array of limited 

sampling 

Frequency of 

MPA 

measure: day 

2, 5, 28 

Assay used: 

HPLC 

Health 

outcome: 

creatinine 

albumin 

Length of 

followup: 

28d 

Author: 

Johnson 

Year: 

1998 

Country: 

USA 

Aim: The purpose of this 

study was to 

determine the effect 

of renal function on 

the elimination and 

disposition of MPA 

and its MPAG after 

oral administration of 

the pro-drug 

MMF,and to examine 

hemodialysis 

removal of MPA and 

its MPAG. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case control 

Entered into study: 

31 

Analyzed: 31 

Population: 

Patients with 

varing degree of 

renal function 

Organ

transplanted: 

Kidney (Renal) 

Age: 44.5 +/- 

15.9, 41.7+/- 

10.3, 43.8 +/- 

10.8, 45.3 +/- 

15.0, 45.3 +/- 8.5 

respectively in 

Groups1-5 

% Male: 74 

83.3, 66.6, 100, 

57.1,66.6 

respectively in 

Groups 1-5 

Weight: 

80.2 +/- 10.3, 

74.9 +/- 15.6, 

103.7 +/- 31.2, 

81.8 +/- 19.0, and 

72.7 +/- 12.1 

respectively in 

groups 1-5 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g 

Prospective dose

adjustment

planned: No

Concomitant

medications: 

None 

Form 

measured: 

MPA, MPAG 

Method of 

measurement: 

Maximum 

concentration, 

Full AUC(0-24h) 

and AUC(0-96h)

Assay used: 

HPLC 

Frequency of 

MPA 

measure: 24 h 

and 96 h after 

administration

Health 

outcome:

elimination 

and 

disposition 

of MPA and 

its MPAG,

Hemodialysi

s removal of 

MPA and its 

MPAG 

Length of 

followup: 

 96h 
C-18

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Kaplan 

Year: 

1999 

Country: 

USA 

Aim: 

To examine the 

protein binding and 

free concentrations 

of MPA in 23 adult 

renal transplant 

patients, 8 of whom 

had chronic renal 

insufficiency 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

23 

Analyzed: 

23 

Population: 

23 Renal 

transplant 

recipients; 8 with 

chronic renal 

insufficiency 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range 46.7 +/- 

9.2 y for chronic 

renal subjects 

43.3 +/- 8.6 For 

renal patients 

without chronic 

insufficiency 

% Male: 37.5 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1.75 +/- 0.3 

g/day 

Prospective dose

adjustment

planned: No 

Concomitant

medications: 

NR 

Form 

measured: 

MPA 

MPAG 

fMPA 

Method of 

measurement: 

abbreviated 

AUC0-12 (based 

on LSS of Co, 

C20, C40, C75, 

C120) 

Frequency of 

MPA 

measure: 

once (>2wk) 

Assay used: 

HPLC 

Health 

outcome: 

adverse 

events 

leucopenia 

abdominal 

pain 

Length of 

followup: 

>2w 

Author: 

Kiberd 

Year: 

2004 

Country: 

Canada 

Aim: 

To examine whether 

early exposure to 

MPA predicts later 

outcomes 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

94 

Analyzed: 

day 3: 94, 

day 5: 86, 

day 7: 58 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 48 +/- 13y 

% Male: 70 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 2 g/day fixed 

Prospective dose

adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Prednisone 

Neoral 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

C2 

AUC0-12

(as predicted 

by LSS of C0, 

C1, C2, C4) 

Frequency of 

MPA 

measure: day 

3, 5, 7 and up 

to 3m 

Assay used: 

HPLC 

Health 

outcome: 

acute 

rejection 

toxicity 

Length of 

followup: 

3m 
C-19

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Kreis 

Year: 

2000 

Country: 

14 European 

centres 

Aim: 

Evaluate the clinical 

activity and safety of 

sirolimus in 

association with 

MMF and steriods 

compared with CsAMMF steroid therapy 

in human renal 

transplantation 

Comparison of 

monitored patients 

with others: No 

Study design: 

RCT 

Entered into study: 

Condition 1 SIR: 40 

Condition 2 CsA: 38 

Analyzed: 

Condition 1 SIR: 40 

Condition 2 CsA: 38 

Population: 

First renal tx 

recipients 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range for entire 

population SIR: 

43.5 +/- 10.9 (22-

62); CsA: 42.9 +/- 

11.4 (18-60) 

% Male: Entire 

population SIR: 

70; CsA: 71 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1g BID 

Prospective dose

adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Corticosteroids 

Sirolimus 

Form 

measured: 

MPA 

Method of 

measurement: 

trough 

Frequency of 

MPA 

measure: 

weekly 

Assay used: 

EMIT 

Health 

outcome: 

trough VS 

rejection 

Length of 

followup: 

6m 

Author: 

Krumme 

Year: 

1998 

Country: 

Germany 

Aim: 

Whether blood levels 

of MPA have an 

impact on the 

outcome after renal 

transplantation, such 

as on the incidence 

of acute rejection as 

well as on the 

incidence of infection 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

48 

Analyzed: 

48 

Population: 

Consecutive renal 

tx recipients 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range 46 +/-11y 

% Male: 71 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1g BID 

Prospective dose

adjustment

planned: Yes 

based on MPA 

plasma levels and 

clinical indicators 

Concomitant

medications: 

Cyclosporine 

Methylpred. 

Form 

measured: 

MPA 

Method of 

measurement: 

 trough levels 

Frequency of 

MPA 

measure: 6 to 

24 samples/ 

patient 

Assay used: 

EMIT 

Health 

outcome: 

rejection 

infection 

urinary 

infection 

Length of 

followup: 

2m 
C-20

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Kuriata - 

Kordek 

Year: 

2002 

Country: 

Poland 

Aim: 

To investigate the 

realtionship between 

PK of MPA and risk 

of developing 

adverse events or 

acute rejection 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case control 

Entered into study: 

Condition I: 12 

patients with acute 

rejection 

Condition II: 27 

patients without 

acute rejection 

Analyzed: 

NR 

Population: all 

adult kidney tx 

recipients 

Organ

transplanted: 

Kidney (Renal) 

Age: Inclusion 

requirement 

group I: 38.12 +/- 

9.5 y, group II: 

38.52 +/- 9.21y 

% Male: 38.5 

Weight: 

Group I: 68.46 +/- 

11.23, 

Group II: 62.89 

+/- 12.41 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 2.0 g/day 

Prospective dose

adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

C0, C40, C60, 

C120, Cmax 

Frequency of 

MPA 

measure: 14 

days - 12 

months 

Assay used: 

HPLC 

Health 

outcome: 

acute 

rejection 

side effects 

leucopenia 

anemia 

GI 

symptoms 

Length of 

followup: 

12m 

Author: 

Kuypers 

Year: 

2004 

Country: 

Belgium 

Aim: 

To examine whether 

the PK parameter of 

tac and MPA reflect 

their clinical efficacy 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

100 

Analyzed: 

NR 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean for entire 

population 

median 51.5y 

% Male: 59 

Weight: 

Mean 69.2 +/- 

13.1 kg at 

baseline 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 0.5 g BID or 

1 g BID 

Prospective dose

adjustment

planned: Yes 

based on clinical 

indicators 

Concomitant

medications: 

Tacrolimus 

Methylpred. 

Daclizumab 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

Cmax 

AUC0-12

Frequency of 

MPA 

measure: day 

7, 42, 90, 180, 

360 and month 

3, 6, 12 

Assay used: 

EMIT 

Health 

outcome: 

acute 

rejection 

infection 

leucopenia 

anemia 

Length of 

followup: 

12m 
C-21

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Kuypers 

Year: 

2003b 

Country: 

Belgium 

Aim: 

To identify a possible 

relation between PK 

of MPA adn clinical 

outcomes 

Comparison of 

monitored patients 

with others: No 

Study design: 

Non-randomized 

controlled trial 

Entered into study: 

33 

Analyzed: 

33 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 49.4 +/- 

13.1y 

% Male: 57.6 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g BID 

Prospective dose

adjustment

planned: No 

Concomitant

medications: 

Tacrolimus 

Daclizumab 

Methylpredisolone 

Form 

measured: 

MPA 

MPAG 

AcMPAG 

fMPA 

Method of 

measurement: 

C0, Cmax, 

AUC0-12 (as 

predicted by 

LSS of C0, 

C40m, C2h) 

Frequency of 

MPA 

measure: day 

3, 7, 10, 14, 

28, week 6, 8, 

10, 12, 14, 

month 4,6, 9, 

12 

Assay used: 

HPLC 

Health 

outcome: 

rejection 

diarrhea 

leucopenia 

anemia 

Length of 

followup: 

12m 

Author: 

Kuypers 

Year: 

2003a 

Country: 

Belgium 

Aim: 

To assess whether 

long term changes in 

MPA exposure and 

Tac and 

corticosteroids are 

dose dependent and 

not reflected through 

plasma 

concentration 

Comparison of 

monitored patients 

with others: No 

Study design: 

Non-randomized 

controlled trial 

Entered into study: 

100 

Analyzed: 

NR 

Population: 

>17 and received 

a primary or 

secondary 

cadaberic donor 

kidney 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean for entire 

population 

meidan 51.5y 

% Male: 59 

Weight: 

Mean 69.2 +/- 13 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g/day or 2 

g/day 

Prospective dose

adjustment

planned: No 

Concomitant

medications: 

Methylpredisolone 

Tacrolimus 

Daclizumab (31 

patients) 

Form 

measured: 

MPA 

Method of 

measurement: 

C0, Cmax, 

AUC0-12

Frequency of 

MPA 

measure: day 

7, week 6, 

month 3 and 

12 

Assay used: 

EMIT 

Health 

outcome: 

biopsy 

proven 

rejection 

survival 

diarrhea 

Length of 

followup: 

12m 
C-22

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Le Meur 

Year: 

2007 

Country: 

France 

Aim: 

Trial of recipients 

randomized to 

receive either FD 

MMF or a CC 

regimen in which 

MMF dose 

adjustments were 

calculated to reach 

predefined MPA 

target levels

Comparison of 

monitored patients 

with others: 

Yes, versus 

predetermined 

dosage schedule 

Study design: 

RCT 

Entered into study: 

CC: 70 

FD: 67 

Analyzed: 

CC: 65 

FD: 65 

Population: 

Consecutive 

recipients of a 

first or second 

allograft 

Organ

transplanted: 

Kidney 

Age: 

CC group: 50 

+/- 14 

FD group 49 +/- 

13 

% Male: 

CC group: 71 

FD group 58 

Weight: 

NR 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 

FD: 1 g BID 

CC: Days 1-7, 1 

g BID, then target 

dose = 40 mg*h/L 

Prospective dose

adjustment

planned: 

Yes - based on 

MPA (or 

metabolite) blood 

levels 

Concomitant

medications: 

Cyclosporine 

Methylpred. 

Basiliximab 

Trimethoprimsulfamethoxazole 

Form 

measured: 

MPA 

Method of 

measurement: 

Abbreviated 

AUC: 20m, 1h, 

3h 

Frequency of 

MPA 

measure: 

Days 7, 14, 

months 1, 3, 

6, 12 

Assay used: 

HPLC 

Health 

outcome: 

Treatment 

failure 

(composite 

of death, 

graft loss, 

acute 

refection 

and MMF 

discontinu

ation) 

Acute 

rejection 

Adverse 

events 

Length of 

followup: 

12m 

Author: 

Lu 

Year: 

2005 

Country: 

China 

Aim: 

To assess influence 

of CsA and Tac on 

MPA and correlate 

PK parameters, 

patient 

characteristics and 

clinical outcomes 

Comparison of 

monitored patients 

with others: No 

Study design: 

Non-randomized 

clinical trial 

Entered into study: 

29 

Analyzed: 

29 

Population: 

Chinese 

recipients of a 1st

kidney 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 40.0 +/- 

12.0y 

% Male: 58.6 

Weight: 

Mean 58.0 +/- 

10.0 kg 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1000 mg 

BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Tacrolimus 

Form 

measured: 

MPA 

Method of 

measurement: 

AUC(0-12h)

Frequency of 

MPA measure: 

NR 

Assay used: 

HPLC 

Health 

outcome: 

acute 

rejection 

Length of 

followup: 

1m 
C-23

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Lu 

Year: 

2006 

Country: 

China 

Aim: 

To investigate the 

relationship between 

clinical events and 

the PK of MPA in 

adult renal transplant 

patients. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

37 

Analyzed: 

37 

Population: 

first cadaveric 

renal 

transplantation 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 34.1 + - 

7.1y 

Range 18 to 64y 

% Male: 65% 

Weight: Inclusion 

requirement 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: weight 

directed dosage 

(50 kg: 2.0 g/day) 

starting 2 days 

before 

transplantation 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators dose 

adjusted 

according to drug 

tolerance and 

related side 

effects 

Concomitant

medications: 

Cyclosporine 

CsA, Neoral 

steroids 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

Cmax 

C60 

AUC0-12

Frequency of 

MPA measure: 

MMF PK profiles 

from 0 (predose 

or Cmin), 0.4 (C 

30), 1 (C60). 

1.5, 2, 2.5, 4, 6, 

8, 10, 12 hour 

samples. MMF 

trough 

concentrations 

measured 

before MMF 

dosage on day 

4, 7, 21, & 28 as 

well as 1.5, 2, 3, 

and 6 months. 

Assay used: 

HPLC 

ROC curve 

analysis 

Health 

outcome: 

acute 

rejection 

(biopsy 

proven) 

infection in 

different 

organs with 

various 

pathogens, 

hematologic 

events, 

mainly 

leukopoenia 

and 

thrombocytopenia, 

GI 

symptoms, 

none of 

which were 

severe 

diarrhea 

Length of 

followup: 

6m 

Author: 

Lu 

Year: 

2004 

Country: 

China 

Aim: 

To investigate 

relation between 

clinical events and 

PK of MPA in 

Chinese kidney 

transplant recipients 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

22 

Analyzed: 

22 

Population: 

Adults of first 

cadaver kidney tx 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 36 +/- 7.1y 

Range 18-57y 

% Male: 54.5 

Weight: 

Not reported 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: weight 

directed 50 kg 

2 g/day 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Cyclosporine 

Form 

measured: 

MPA 

Method of 

measurement: 

Predose 

concentration 

AUC(0-12h) 

Frequency of 

MPA measure: 

2 days before 

transplant, 14 

days after 

transplant 

Assay used: 

HPLC 

RP-HPLC 

Health 

outcome: 

toxicity 

acute 

rejection 

Length of 

followup: 

6m 
C-24

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Maes 

Year: 

2003 

Country: 

Belgium 

Aim: 

To explore GI tract in 

MMF treated patients 

with diarrhea 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

26 

Analyzed: 

26 

Population: 

Transplant 

recipients with 

persistent afebrile 

diarrhea 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 46 +/- 15y 

Range 18 – 70y 

% Male: 46.2 

Weight: 

Mean 66.8 +/- 

13.8 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1.6 +/- 0.5 

g/day, range 1 – 3 

g/day 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Methylpred. 

Form 

measured: 

MPA 

MPAG 

AcMPAG 

free MPA 

Method of 

measurement: 

Co

Frequency of 

MPA measure: 

NR 

Assay used: 

NR 

Health 

outcome: 

 bile acid 

malabsorption

colonic 

transit time 

infection 

Length of 

followup: 

2y 

Author: 

Mandla 

Year: 

2006 

Country: 

Norway 

Aim: 

TDM of MPA with 

CsA ar Tac was 

investigated in renal 

tx patients 

Comparison of 

monitored patients 

with others: No 

Study design: 

Non-randomized 

Controlled Trial 

Entered into study: 

Condition 1 68 CsA 

Condition 2 10 Tac 

Analyzed: 

78 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: Mean 54y 

Range 19 -77y 

% Male: 73.1 

Weight: 

Mean 74 kg 

Range 49-139 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1g 2 times 

day in combined 

kidney plus 

pancreas 

transplant 

patients 1 g 3 

times a day 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Methylpred. 

Prednisone 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

Predose 

concentration 

Frequency of 

MPA measure: 

2-3/wk for first 4 

wks, then 1-2/wk 

up to 3 months 

Assay used: 

HPLC 

 Automated 

sequential trace 

enrichment of 

dialysis 

Health 

outcome: 

acute 

rejection 

Length of 

followup: 

3m 
C-25

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Meiser 

Year: 

1999a 

Country: 

Germany 

Aim: 

To investigate the 

efficacy of Tac and 

MMF combination 

therapy as primary 

immunosupression. 

Comparison of 

monitored patients 

with others: Phase 

I, fixed dose patients 

compared to phase 

II, patients with dose 

adjusted for MPA 

level 

Study design: 

Non-randomized 

Controlled Trial 

Entered into study: 

Condition 1 Phase I 

15 

Condition 2 Phase II 

30 

Analyzed: 

Condition 1 Phase 1 

15 

Condition 2 Phase II 

30 

Population: 

Consecutive 

patients 

undergoing 

primary orthotopic 

cardiac 

transplantation 

Organ

transplanted: 

Heart (Cardiac) 

Age: Inclusion 

requirement >18y 

Mean Phase I 

50.6 +/- 11.4, 

Phase II 54.01 

+/- 8.9 

Range Phase I 

18-64, Phase II 

21-66 

% Male: Phase I 

87%, Phase II 

77% 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: Phase I 1 

g BID, Phase II 

target level 2.5 to 

4.5 ug/mL 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels Phase II 

Concomitant

medications: 

Tacrolimus 

Methylpred. 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

Frequency of 

MPA measure: 

Daily X 3 weeks, 

then biweekly 

Assay used: 

EMIT 

Health 

outcome: 

rejection 

survival 

Length of 

followup: 

Phase I: 

522 (432-

616)d, 

Phase II: 

273 (133-

388)d 
C-26

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Meiser 

Year: 

1999b 

Country: 

Germany 

Aim: 

Assess the efficacy 

of Tac and 

mycophenolate as 

primary therapy 

following cardiac 

transplantation 

Comparison of 

monitored patients 

with others: Phase 

I, fixed dose patients 

compared to phase 

II, patients with dose 

adjusted for MPA 

level 

Study design: 

Non-randomized 

Controlled Trial 

Entered into study: 

Condition 1 PhaseI: 

15 

Condition 2 Phase II: 

30 

Analyzed: 

Condition 1 Phase I: 

15 

Condition 2 Phase II: 

30 

Population: 

consecutive 

patients 

undergoing 

orthotopic cardiac 

transplantations 

Organ

transplanted: 

Heart (Cardiac) 

Age: Inclusion 

requirement 

Phase I & II: >18y 

Range Phase I: 

50.6 +/- 11.4 (18-

64); Phase II: 

54.1 +/- 8.9 (21-

66) 

% Male: Phase I: 

87; phase II: 77 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: Phase I: 1 

g/day BID 

Phase II: 2.5 to 

4.5 ug/ml 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels Phase II 

Concomitant

medications: 

Tacrolimus 

Prednisone 

Methylpred. 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

Frequency of 

MPA measure: 

Phase I: NR 

Phase II: 

Monthly 

Assay used: 

EMIT 

Health 

outcome: 

rejection 

toxicity 

Length of 

followup: 

Phase I: 

696 ± 62d 

(606-790) 

Phase II: 

436 ± 88d 

(175-562) 

Author: 

Merkel 

Year: 

2005 

Country: 

Germany 

Aim: 

To use MMF to 

prevent rejection in 

renal transplant 

patients 

Comparison of 

monitored patients 

with others: No 

Study design: 

Retrospective Cohort 

Entered into study: 

35 

Analyzed: 

35 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 44 +/- 13.6y 

Range 13– 63y 

% Male: 68.6 

Weight: 

Mean 72.9 +/- 

14.3 

Range 47-104 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 0.5-1.0 g 

BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Corticosteroids 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

trough levels 

Frequency of 

MPA measure: 

NR 

Assay used: 

HPLC 

Health 

outcome: 

acute 

rejection 

drug 

reactions 

(diarrhea) 

Length of 

followup: 

16m, 

mean 5.7m 
C-27

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Morgera 

Year: 

1998b 

Country: 

Germany 

Aim: 

MMF PK in renal 

transplant recipients 

on peritoneal 

dialysis. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Prospective Cohort 

Entered into study: 

Condition 1 delayed 

graft function n=3 

Condition 2 

recovering renal 

function n=2 

Analyzed: 

Condition 1 delayed 

graft function n=3 

Condition 2 

recovering renal 

function n=2 

Population: 

Early post 

transplant 

patients on 

dialysis 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range 25 – 60y 

% Male: 20% 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g BID; 

Two 12 hour 

periods, once 

before and once 

after peritoneal 

dialysis. 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Methylpred. 

Oxacillin 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

NR 

Frequency of 

MPA measure: 

Before and 8 

times after 

dosage in 12 

hour period 

Assay used: 

HPLC semiautomatic 

Health 

outcome: 

GFR 

Length of 

followup: 

2d 

Author: 

Morgera 

Year: 

1998a 

Country: 

Germany 

Aim: 

PK of MMF in renal 

transplant patients 

on dialysis 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

Condition 1 delayed 

graft function n=3 

Condition 2 

recovering graft 

function n=2 

Analyzed: 

Condition 1 delayed 

graft function n=3 

Condition 2 

recovering graft 

function n=2 

Population: 

Early post 

transplant 

patients on 

dialysis 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range 25 to 60y 

% Male: 20% 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g BID; 

Two 12 hour 

periods, once 

before and once 

after peritoneal 

dialysis. 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Methylpred. 

Oxacillan 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

NR 

Frequency of 

MPA measure: 

before and 8 

times after 

dosage in 12 

hour period 

Assay used: 

HPLC 

Health 

outcome: 

GFR 

Length of 

followup: 

2d 
C-28

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Mourad 

Year: 

2001b 

Country: 

Belgium 

Aim: 

Assess the 

pharmacokinetic/pha

rmacodynamic 

(PK/PD) relationship 

for MPA in kidney 

transplant patients 

recieving low-dose 

MMF (500 mg twice 

a day) in 

combination with 

Tac. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

51 

Analyzed: 

51 

Population: 

Adult, kid tx on 

low dose MPA 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range 32-68y 

Median 49y 

% Male: 57 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 500 mg 

BID + adjustment 

for side effects 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Tacrolimus 

Corticosteroids 

Form 

measured: 

MPA 

Method of 

measurement: 

Frequency of 

MPA measure: 

Immediate 

stabilized if side 

effect or rejected 

+ 3m 

Assay used: 

EMIT 

Health 

outcome: 

rejection 

side effects 

thrombocytopenia 

esophagitis 

lecopenia 

anemia 

GI 

symptoms 

Diarrhea 

Length of 

followup: 

3m 

Author: 

Mourad 

Year: 

2001a 

Country: 

Belgium 

Aim: 

Investigate the 

relationship between 

the clinical events 

and the PK of MPA 

in adult renal 

transplantation 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

31 

Analyzed: 

31 

Population: 

Adult kidney tx 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 43y 

Range 16-67y 

% Male: 55 

(17/31) 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g BID 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Cyclosporine 

anti-thymocyte 

globulin 

steroids 

Form 

measured: 

MPA 

Method of 

measurement: 

Co, C30m, AUC0-12 

Frequency of 

MPA measure: 

early after tx, 3 

months and at 

every clinical 

event 

Assay used: 

EMIT 

HPLC 

Health 

outcome: 

side effects 

rejection 

esophagitis 

leucopenia 

diarrhea 

anemia 

thrombocytopenia 

Length of 

followup: 

3m 
C-29

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Mourad 

Year: 

2000 

Country: 

Belgium 

Aim: 

Evaluate the 

analytical 

performances of this 

new EMIT assay, to 

determine the main 

PK parameters of 

MPA in renal 

transplantation, and 

finally, to evaluated a 

possible relationship 

between 

pharmacodynamics 

and 

pharmacokinetics of 

MPA (correlation) 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

7 

Analyzed: 

7 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 46y 

Range 33-57y 

% Male: 29 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1g BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

 prednisolone 

Form 

measured: 

MPA 

Method of 

measurement: 

C0- 

AUC0-12, 

Frequency of 

MPA measure: 

week 1,4,12 

Assay used: 

EMIT 

Health 

outcome: 

acute 

rejection 

side effects 

Length of 

followup: 

12w 

Author: 

Mudge 

Year: 

2004 

Country: 

Australia 

Aim: 

To study the effect of 

iron on MMF 

absorption in renal 

transplant patients 

Comparison of 

monitored patients 

with others: No 

Study design: 

RCT 

Entered into study: 

45 

Analyzed: 

40 

Population: 

white 98%, BMI 

25.1 +/- 3.7 

kg/m2; only adults 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 45.2 +/- 

13.2y 

% Male: 55 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

AUC0-12 (as 

predicted by 

LSS of C0, C1, 

C3, C6) 

Frequency of 

MPA measure: 

day 5 

Assay used: 

HPLC 

Health 

outcome: 

acute 

rejection 

toxicity 

GI 

symptoms 

Length of 

followup: 

7m 
C-30

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Naesens 

Year: 

2006 

Country:

Belgium 

Aim: 

To determine the 

relationship between 

single nucleotide 

polymorphisms in the 

MRP2 genes and 

MPA PK 

Comparison of 

monitored patients 

with others: No 

Study design: 

Prospective Cohort 

Entered into study: 

Condition 1 MRP2 

carriers 41 

Condition 2 MRP2 

non carriers 54 

Analyzed: 

Condition 1 MRP2 

carriers 41 

Condition 2 MRP2 

non carriers 54 

Population: 

caucasian de 

novo renal 

allograft recipients 

Organ

transplanted: 

Kidney (Renal) 

Age: Inclusion 

requirement >17 

Mean 51.3 +/- 

14.1y 

% Male: 60 

Weight: 

Mean 68.7 +/- 

13.4 kg 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 0.5 or 1 g 

BID 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Tacrolimus 

Corticosteroids 

Daclizumab for 29 

subjects 

Oral Methylpred. 

Form 

measured: 

MPA 

Method of 

measurement: 

 CL/F apparent 

steady-state 

total body 

clearance 

Frequency of 

MPA measure: 

day 7(12 hour 

AUC),day 42(2 

hour AUC),day 

90(4 hour 

AUC),day 360(4 

hour AUC) 

Assay used: 

EMIT 

Health 

outcome: 

liver 

dysfunction 

Length of 

followup: 

360d 

Author: 

Naito 

Year: 

2006 

Country:

Japan

Aim: 

To obtain information 

on PK of 

MPA/MPAG and 

their interactions with 

CNIs 

Comparison of 

monitored patients 

with others: No 

Study design: 

Non-randomized 

Controlled Trial 

Entered into study: 

9 in Tac group, 

3 in CNI group, 

13 in CsA group 

Analyzed: 

NR 

Population: 

Japanese renal tx 

recipients 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range 14 – 60y 

% Male: 64 

Weight: 

Mean 59.2 kg 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 250-1750 

mg/day 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

correlation 

between MMF 

dose 

Blood Co 

Regression 

analysis 

Frequency of 

MPA measure: 

NR 

Assay used: 

HPLC 

Health 

outcome: 

serum 

creatinine 

Length of 

followup: 

>6m 
C-31

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Okamoto 

Year: 

2005 

Country: 

Japan 

Aim: 

To analyze 

usefulness of 

monitoring MPA to 

optimize therapy 

Comparison of 

monitored patients 

with others: No 

Study design: 

Non-randomized 

Controlled Trial 

Entered into study: 

67 

Analyzed: 

Entire population 67 

(PK studies of MPA 

performed in 46 

patients) 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 38 +/- 14y 

% Male: NR 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 25 mg/kg 

initially, then 

adjusted 

afterwards 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels and on 

adverse events 

and TDM 

Concomitant

medications: 

Cyclosporine 

n=35 

Tacrolimusn=32 

Form 

measured: 

MPA 

Method of 

measurement: 

Co, , 

AUC0-9

Frequency of 

MPA measure: 

2 weeks and 4 

weeks after 

transplant 

Assay used: 

EMIT 2000 

Health 

outcome: 

acute 

rejection 

infection 

GI 

Length of 

followup: 

NR 

Author: 

Orlando 

Year: 

2006 

Country: 

Italy 

Aim: 

Increase 1.5 g/day 

MMF to 2 g/day in 

patients with CNI 

chronic toxicity. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

42 

Analyzed: 

41 

Population: 

Adult liver 

transplanted 

patients with CNI 

related adverse 

effects. 

Organ

transplanted: 

Liver 

Age: 

Mean 60.1y 

Range 35 – 67y 

% Male: 81% 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) MMF 

Dose: 250 mg per 

os BID increased 

weekly by 500 mg 

to dose of 1500 

mg/day 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators With a 

diagnosis of AR 

then MMF dose 

was adapted 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

Frequency of 

MPA measure: 

monthly 

Assay used: 

EMIT 2000 

Health 

outcome: 

renal 

function 

creatinine 

levels 

trigycerides 

cholesterol 

diastolic 

blood 

pressure 

acute 

rejection 

Length of 

followup: 

mean 61.5 

± 6.1m 
C-32

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Pape 

Year: 

2004 

Country: 

Germany 

Aim: 

To determine 

whether long term 

monitoring in 

pediatric renal graft 

recipients improves 

quality of 

immunosuppression 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

42 

Analyzed: 

NR 

Population: 

Children and 

adults – min 1y 

after renal tx 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean for entire 

population 

median 9.4y 

Range 1.4 - 15.1y 

% Male: 64.3 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 600 mg/m2 

BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

Predose 

concentration 

Frequency of 

MPA measure: 

every 3 months 

Assay used: 

LC-MS 

Health 

outcome: 

NR 

Length of 

followup: 

2y 

Author: 

Pawinski 

Year: 

2006a 

Country: 

Poland 

Aim: 

To examine the 

ability of PK to 

discriminate between 

patients with and 

without acute 

rejection 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

51 

Analyzed: 

51 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 48y 

Range 17–62y 

% Male: 52.9 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Prednisone 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

C0, Cmax, AUC0-

12 

Frequency of 

MPA measure: 

at day 7, 6 - 8 

weeks and 3 m 

Assay used: 

HPLC 

Health 

outcome: 

acute 

rejection 

Length of 

followup: 

3m 
C-33

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Pawinski 

Year: 

2006b 

Country: 

Poland 

Aim: 

To investigate the 

effect of time on PK 

of MPA in early 

posttransplant period 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

33 

CsA: 23 patients 

Tac: 10 patients 

Analyzed: 

33 

Population: 

Adult renal tx 

recipients 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range 17–62y 

% Male: 45.5 

Weight: Range 

40-86 kg 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 0.5 - 2 

g/day 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators toxicity 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Prednisone 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

C0, AUC0-2, 

AUC0-12 

concentration 

Frequency of 

MPA measure: 

1wk, 2m, 3m 

Assay used: 

HPLC 

Health 

outcome: 

acute 

rejection 

leucocyte 

cell count 

hemotocrit 

Length of 

followup: 

3m 

Author: 

Pillans 

Year: 

2001 

Country: 

Australia 

Aim: 

Assess the 

relationship between 

a single four-point 

MPA AUC 

measurement 

performed in the first 

week after 

transplant, as well as 

median trough 

cyclosporin 

concentration before 

rejection or during 

the first month and 

clinical outcomes in 

the first month. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

27 

Analyzed: 

27 

Population: 

Caucasian from 

single center 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range 21-65 y 

% Male: 78 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 2 g/day 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

AUC0-12 (as 

predicted by 

LSS C0, C1, C3, 

C6 ) 

Frequency of 

MPA measure: 

once (day 3-5) 

Assay used: 

HPLC 

Health 

outcome: 

Biopsyproven 

acute 

rejection 

Gastrointest

inal adverse 

events 

Length of 

followup: 

1m 
C-34

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Reggiani 

Year: 2005 

Country: 

Italy 

Aim: 

To evaluate Tac and 

MMF with steroids 

and to evaluate PK 

of MPA 

Comparison of 

monitored patients 

with others: No 

Study design: 

RCT 

Entered into study: 

30 

Group A: 12 patients 

Group B: 18 patients 

Analyzed: 

30 

Population: 

Liver transplant tx 

Organ

transplanted: 

Liver 

Age: 

Mean for entire 

population group 

A: 49.7 +/- 4.6, 

group B: 50.4 +/- 

8.9 

% Male: Entire 

population 70, 

group A: 66.7, 

group B: 72.2 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 750 mg 

BID 1st month, 

500 mg BID > 1 

month 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Tacrolimus group 

A and B 

Methylpred. group 

B 

Prednisone group 

B 

Form 

measured: 

MPA 

Method of 

measurement: 

AUC0-12 

Frequency of 

MPA measure: 

1wk and 1m 

Assay used: 

NR 

Health 

outcome: 

leucopenia, 

low platelet 

count, GI 

and 

neurological 

symptoms 

Length of 

followup: 

mean 31 +/- 

7m 

Author: 

Ringe 

Year: 

2001 

Country: 

Germany 

Aim: 

Pilot study to 

investigate a 

novel steroid-free 

immunosuppressive 

regimen after 

clinical liver 

transplantation 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

30 

Analyzed: 

30 

Population: 

NR 

Organ

transplanted: 

LIver 

Age: 

Median 51.9y 

Range 15–66y 

% Male: 70 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 2315 to 

2320 mg/kg/day 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Tacrolimus 

Form 

measured: 

MPA 

Method of 

measurement: 

12 hr post dose 

Frequency of 

MPA measure: 

Daily 

Assay used: 

HPLC 

Health 

outcome: 

acute 

rejection 

diarrhea 

Length of 

followup: 

2y 
C-35

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Satoh 

Year: 

2006 

Country: 

Japan 

Aim: 

To investigate MPA 

chronopharmacokine

tics and relation 

between MPA 

circadian exposure 

and incidence of 

acute rejection 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

30 

Analyzed: 

30 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 41.2 +/- 

2.1y 

Range 21–66y 

% Male: 50 

Weight: 

Mean 56.4 +/-1.9 

Range (37.0-81.0) 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 2 g/day 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators GI 

symptoms 

Concomitant

medications: 

Tacrolimus 

Methylpred. 

Corticosteroids 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

Cmax 

AUC0-12

Frequency of 

MPA measure: 

13 samples in 

24 hrs, just prior, 

1, 2, 3, 6, 9, and 

12 hr after each 

dose (2 doses a 

day) 

Assay used: 

HPLC 

Health 

outcome: 

acute 

rejection 

diarrhea 

nausea 

abdominal 

pain 

vomiting 

Length of 

followup: 

NR 

Author: 

Satoh 

Year: 

2005 

Country: 

Japan 

Aim: 

To investigate the 

influence of MMF on 

incidence of acute 

rejection and 

infectious 

complications 

Comparison of 

monitored patients 

with others: No 

Study design: 

Prospective Cohort 

Entered into study: 

66 

Analyzed: 

66 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean for entire 

population AZA: 

37.9 +/- 11.5 

MMF: 44.3 +/- 

11.6 

% Male: Entire 

population AZA: 

54.5, MMF: 59.1 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1.0 – 2 

g/day 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Tacrolimus 

Methylpred. 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

AUC(0-12h)

Frequency of 

MPA measure: 

just before dose 

and 1,2,3,6,9 

and 12 h after 

morning oral 

administration 

Assay used: 

HPLC 

Health 

outcome: 

viral 

infection 

acute 

rejection 

CMV 

infections 

Varicella 

Zoster 

Malignancy 

related 

EpsteinBarr 

Adenovirus 

hemorrhagic 

cystitis 

Length of 

followup: 

28d 
C-36

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Shaw 

Year: 

2000 

Country: 

USA 

Aim: 

Possibility of an 

effect of ethnicity on 

the PK of MPA 

Comparison of 

monitored patients 

with others: Yes 

Two set s of 

monitored patients: 

AUC controlled vs 

MPA Co

Study design: 

Prospective Cohort 

Entered into study: 

African American: 13 

Caucasian: 20 

Analyzed: 

NR 

Population: 

Adult renal 

transplant 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range 47 +/-9.7y 

% Male: 70 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1g BID 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels AUC level, 

predose trough 

level 

Concomitant

medications: 

Neoral Steriods 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

Co 

Cmax 

AUC0-12 (as 

predicted by 

LSS of Co, C20, 

C40, C75, C120)

Frequency of 

MPA measure: 

day 4,7,14,28,90 

Assay used: 

HPLC 

Health 

outcome: 

Rejection, 

leukopenia, 

gastrointestinal toxicity 

Length of 

followup: 

90d 

Author: 

Shaw 

Year: 

1997 

Country: 

USA 

Aim: 

PK of MPA in Renal 

Transplant patients 

with delayed graft 

function 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

8 

Analyzed: 

8 

Population: 

recent kidney 

transplant with 

delayed graft 

function having 

one hemodialysis 

within previous 24 

hr. 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range 31–58y 

% Male: 50% 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) oral 

MMF 

Dose: 3 g/day for 

28d 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Methylpred. 

azathioprine 

Form 

measured: 

MPA 

MPAG 

fMPA MPA free 

faction 

Method of 

measurement: 

Predose 

concentration 

MPA free faction 

%creatinine 

linear regression 

model 

Frequency of 

MPA measure: 

predose plus 7 

X/d once a wk 

for 5 wks 

Assay used: 

HPLC 

Health 

outcome: 

hemodialysis 

did not lower 

MPA plasma 

concentration

hemodialysis 

id remove 

some MPAG 

from the 

blood 

renal function 

is the primary 

determinant 

of MPAG 

plasma 

concentration

Length of 

followup: 

28d 
C-37

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Smak 

Gregoor 

Year: 

2000b 

Country: 

Netherlands 

Aim: 

Compare the effect 

of conversion to 

either MMF or AZA 

with predisone 

Comparison of 

monitored patients 

with others: No 

Study design: 

RCT 

Entered into study: 

Condition 1 MMF - 

34 

Condition 2 AZA - 30 

Analyzed: 

64 

Population: 

Stable kidney 

recipients on CsA 

and prednisone 1 

year post 

transplant 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean for entire 

population MMF - 

46; AZA - 44 

Range for entire 

population MMF - 

21-73; AZA - 22-

67 

% Male: Entire 

population MMF - 

56, AZA - 60 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1g BID 

Prospective

dose adjustment

planned: No 

prescribed plan; 

only if physician 

allows 

Concomitant

medications: 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

C0, C12h 

Frequency of 

MPA measure: 

NR 

Assay used: 

EMIT 

Health 

outcome: 

acute 

rejection 

side effects 

Length of 

followup: 

MMF: 1.61 

+/- 0.6y 

AZA: 1.72 

+/- 0.54y 

Author: 

Smak 

Gregoor 

Year: 

2000a 

Country: 

Netherlands 

Aim: 

Describes the results 

of dose reduction 

and MPA trough 

levels in renal 

tranplant patients 

treated with MMF 

and prednisone 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

27 

Analyzed: 

27 

Population: 

Stable 1y post 

kidney tx 

Organ

transplanted: 

Kidney (Renal) 

Age: 

NR 

% Male: 

NR 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g BID, 

750 mg BID, 500 

mg BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

Trough levels 

Frequency of 

MPA measure: 

4,8,12m 

Assay used: 

EMIT 

Health 

outcome: 

rejection 

Length of 

followup: 

1y 
C-38

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Smak 

Gregoor 

Year: 

1998 

Country: 

Netherlands 

Aim: 

The results of 

monitoring MPA 

trough levels in 

relation to adverse 

events. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

24 

Analyzed: 

15 

Population: 

patients 

converted from 

azathioprine 

cyclosporin and 

prednisone to 

MMF, cyclosporin 

& prednisone 1y 

after transplant 

Organ

transplanted: 

Kidney (Renal) 

Age: 

NR 

% Male: 

NR 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 2 g/day 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

MPA trough 

levels 

Frequency of 

MPA measure: 

3 times over 2 

wks 

Assay used: 

EMIT 

Health 

outcome: 

hair loss 

(alopecia) 

anemia 

Length of 

followup: 

2w 

Author: 

Sugioka 

Year: 

2006 

Country: 

Japan 

Aim: 

To obtain more 

useful information for 

therapeutic drug 

monitoring of MPA 

after MMF dosing in 

Japanese renal 

transplant patients 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

Entire population 83 

Condition 1 63 

Condition 2 20 

Analyzed: 

Condition 1 53 on 

day 14, 50 on day 28 

Condition 2 NR 

Population: 

Recent renal tx 

patients 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range for entire 

population MPA 

group: 7-69y, PSL 

group: 11 - 66y 

% Male: Entire 

population MPA 

group: 65.1 PSL 

group: 55 both: 

62.7 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: MPA 

group: 1000 to 

1500 mg/day 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Form 

measured: 

MPA 

Method of 

measurement: 

 AUC(0-9h)

Frequency of 

MPA measure: 

day 7, 14, 21, 28 

post 

transplantation 

Assay used: 

EMIT 

Health 

outcome: 

leukopenia 

diarrhea 

Length of 

followup: 

28d 
C-39

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Sumethkul 

Year: 

2005 

Country: 

Thailand 

Aim: 

To assess early MPA 

delivery by E-MPS 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

12 

Analyzed: 

12 

Population: 

NR 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 39 +/- 9y 

% Male: 

NR 

Weight: 

Mean 48.1 +/- 

8.8kg 

 

Form given: 

Mycophenolate 

sodium (Myfortic - 

enteric coated, 

EC - delayed 

release) 

Dose: 720 mg 

BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

 AUC(0-12h)

Frequency of 

MPA measure: 

NR 

Assay used: 

HPLC 

Health 

outcome: 

GI side 

effects 

acute 

allograft 

dysfunction 

borderline 

acute 

rejection 

Length of 

followup: 

3 - 8m 

Author: 

Takahashi 

Year: 

1995 

Country: 

Japan 

Aim: 

MMF in the 

prevention of acute 

rejection following 

renal transplant. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Non-randomized 

Controlled Trial 

Entered into study: 

Condition 1 1000 mg 

n=12 

Condition 2 2000 mg 

n= 10 

Condition 3 3000 mg 

n=10 

Analyzed: 

Condition 1 1000 mg 

n = 12 

Condition 2 2000 mg 

n= 9 

Condition 3 3000 mg 

n= 10 

Population: 

Patients receiving 

first renal 

transplant, ≥16y 

Organ

transplanted: 

Kidney (Renal) 

Age: Range: 

37.7–41y 

% Male: 68.75% 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) MMF 

(RS-61443) 

Dose: 1000, 

2000, or 3000 

mg/day 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

 steroids (no 

description) 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

AUC0-12

 

Frequency of 

MPA measure: 

Trough plasma 

levels and 12-

hour AUC were 

monitored at 

weeks 1, 2 & 3. 

Clicial lab 

testing including 

CMV titers was 

performed on a 

weekly or 

biweekly basis. 

Assay used: 

NR 

Health 

outcome: 

patient 

survival 

graft 

survival 

pancytopenia 

gastrointestinal 

disturbances 

numbness 

of limbs & 

tongue 

hemorrhagic 

duodenal 

ulcer

Length of 

followup: 

12wks 
C-40

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Tredger 

Year: 

2004 

Country: 

UK 

Aim: 

To determine a 

target range of MPA 

plasma levels that 

reduced adverse 

events 

Comparison of 

monitored patients 

with others: No 

Study design: 

Prospective Cohort 

Entered into study: 

147 adults, 63 

children 

Analyzed: 

147 adults, 63 

children 

Population: 

Liver allograft 

recipients 

Organ

transplanted: 

Liver 

Age: 

Mean for entire 

population adults 

median: 50.1y, 

children median: 

3.5y 

Range for entire 

population adults: 

16.9 - 71.8y, 

children: 0.3 - 

19.5y 

% Male: Entire 

population adults: 

53.1, children: 

49.2 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: adults: 500 

mg BID then 

increased, 

children: 5 mg/kg 

BID then 

increased 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels to achieve 

therapeuic levels 

and also based 

on clinical 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Form 

measured: 

MPA 

Method of 

measurement: 

 trough levels 

Frequency of 

MPA measure: 

3 assays per 

week 

Assay used: 

EMIT 

Health 

outcome: 

acute 

rejection 

leucopenia 

infection 

GI 

Length of 

followup: 

2y 
C-41

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Tsaroucha 

Year: 

2000 

Country: 

USA 

Aim: 

Determine the 

therapeutic trough 

levels of MPA and 

MPAG in kidney, 

liver and small bowel 

transplant patients 

who received both 

Tac and MMF, in 

order to assess 

potential differences 

in the bioavailability. 

i.e., effectiveness of 

this agent between 

the three groups 

Comparison of 

monitored patients 

with others: No 

Study design: 

Prospective Cohort 

Entered into study: 

Condition 1 liver: 83 

Condition 2 small 

bowel: 15 

Condition 3 kidney: 

25 

Analyzed: 

Condition 1 liver: 83 

Condition 2 small 

bowel: 15 

Condition 3 kidney: 

25 

Population: 

liver, small bowel 

and kidney tx 

Organ

transplanted: 

Kidney (Renal) 

Liver 

Small bowel 

Age: 

Mean for groups: 

liver: 41.4 +/- 

4.6y; small bowel: 

18.7 +/- 3.9y; 

kidney: 44.3 +/- 

2.7y 

% Male: liver: 70; 

small bowel: 40; 

kidney: 52 

Weight: 

Mean liver: 74.2; 

small bowel: 38.7; 

kidney:77.1 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: liver: 

0.0258 g/kg/day 

small bowel: 

0.0822 g/kg/day 

kidney: 0.0194 

g/kg/day 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Tacrolimus 

steroids 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

 trough 

Frequency of 

MPA measure: 

5 to 30 

measures/subje

ct 

Assay used: 

HPLC 

Health 

outcome: 

rejection 

Length of 

followup: 

liver: 165d; 

small 

bowel: 58d; 

kidney: 

373d; all 

post 

transplant 

Author: 

van Besouw 

Year: 

1999 

Country: 

Netherlands 

Aim: 

Observe the effect of 

MMF on 

haematological 

parameters such as 

haemoglobin (Hb), 

leukocytes and 

thrombocytes 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

26 

Analyzed: 

26 

Population: 

Stable renal tx 

patients without 

rejection at 12m 

post tx 

Organ

transplanted: 

Kidney (Renal) 

Age: 

NR 

% Male: 46 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 2 g/day – 1 

g/day 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

 trough 

Frequency of 

MPA measure: 

4m to 8m on 

MPA 16m to 

20m post tx 

Assay used: 

EMIT 

Health 

outcome: 

leukocytes 

decrease in 

Hb 

Length of 

followup: 

8m 
C-42

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

van Gelder 

Year: 

1999 

Country: 

Netherlands 

Aim: 

Provide a data set 

consisting of welldistributed MPA area 

under the curve 

(AUC) data in a 

population of kidney 

transplant recipients, 

using biopsy-proven 

rejection over a 6-

month period after 

transplantation as 

the end point 

Comparison of 

monitored patients 

with others: Three 

target MPA AUC 

values compared 

Study design: 

RCT 

Entered into study: 

154 

Analyzed: 

150 

Population: 

Adult recipients of 

a primary or 

secondary 

cadaveric kidney 

transplant; 

Caucasian L: 

94.1%, I: 91.5%, 

H: 94.2% 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range L: 47.8 +/- 

11.5; I: 46.9 +/- 

13.8; H: 50.6 +/- 

10.5 

% Male: L: 58.8; I: 

63.8; H: 59.6 

Weight: 

Range 

L: 69.8 +/- 12.5 kg 

I: 65.9 +/- 13.1 kg 

H: 67.4 +/- 11.3 

kg 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: L: 16.1 ug 

hr/ml I: 32.2 ug 

hr/ml H: 60.6 ug 

hr/ml 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Corticosteroids 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

Cmax 

AUC0-12

 

Frequency of 

MPA measure: 

day 3,7,11,21,28 

week 8,12,16,20 

Assay used: 

HPLC 

Health 

outcome: 

acute 

rejection 

adverse 

events 

(vomit, 

abdominal 

pain, 

diarrhea 

leukopenia 

pneumonia 

Length of 

followup: 

6m 

Author: 

Wang 

Year: 

1998 

Country: 

China 

Aim: 

Compare the 

efficiency and safety 

of MMF on the 

dosage between 2.0 

g/day and 1.5 g/day 

in order to find 

appropriate doasge 

of MMF 

Comparison of 

monitored patients 

with others: No 

Study design: 

RCT 

Entered into study: 

13 

Analyzed: 

13 

Population: 

Primary cadaveric 

renal tx recipients 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Range 35-59y 

% Male: 54 

Weight: 

Range 35-68 kg 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: Group 1. 

1.0 g BID 

Group 2. 

0.75 g BID 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Cyclosporine 

Corticosteroids 

Methylpred. 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

Cmax 

AUC0-12

Frequency of 

MPA measure: 

day 21 

Assay used: 

HPLC 

Health 

outcome: 

Mild 

rejection, 

adverse 

effects 

Length of 

followup: 

3m 
C-43

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Wang 

Year: 

2007 

Country: 

China 

Aim: 

Explore the PK 

characteristics and 

therapeutic window 

of MPA in elderly 

Chinese recipients to 

establish a practical 

model equation to 

estimate MPA AUC 

in this age group by 

LSS 

Comparison of 

monitored patients 

with others: 

No 

Study design: 

Prospective cohort 

Entered into study: 

Elderly group: 24 

Adult group: 24 

Analyzed: 

Elderly group: 24 

Adult group: 24 

Population: 

Chinese patients, 

elderly group 

versus adult 

group 

Organ

transplanted: 

Kidney 

Age: 

Elderly group: 

65.6 ± 3.6y 

Adult group: 39.6 

± 14.3y 

% Male: 

Elderly group:: 71 

Adult group: 63 

Weight: 

Elderly group: 

61.4 ± 8.6kg 

Adult group: 65.9 

± 10.8kg 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 

First 2-4w: 0.75 g 

BID 

After 2-4w, 0.5 g 

BID 

Prospective dose

adjustment

planned: 

No 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

C0, AUC0-12 

Frequency of 

MPA 

measure: 

Once at 10-

12w 

Assay used: 

HPLC 

Health 

outcome: 

Acute 

rejection 

Severe 

adverse 

events: 

pneumonia, 

leukocytepenia, 

death 

Length of 

followup: 

6m 
C-44

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Weber 

Year: 

2006 

Country: 

Germany 

Aim: 

To estimate MPA 

exposure in pediatric 

renal transplant 

patients 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

Condition 1 : 54 

Condition 2 : 25 

Analyzed: 

Condition 1: 54 

Condition 2: 25 

Population: 

German study: 54 

pediatric renal 

transplant 

patients in the 

German study 

group on MMF 

therapy; 44 had 

primary transplant 

function, 10 had 

delayed graft 

function 

suspension trial: 

25 pediatric renal 

transplant 

recipients in the 

Tricontinental 

MMF trial 

Organ

transplanted: 

Kidney (Renal) 

Age: Inclusion 

requirement NR 

(published in 

previous reports) 

Range for entire 

population 

german study: 

3.17-16.0y, 

suspension trial: 

1.0-16.0y 

% Male: Entire 

population 

German study: 

61.1, suspension 

trial: 68.0, both: 

63.3 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: German 

study: 600 mg/m2 

BSA up to 2 g/day 

suspension trial: 

600 mg/m2 body 

surface area BID 

(up to 1000mg 

BID), 

corresponding to 

1 g MMF BID in 

adult renal 

transplant 

recipients 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine CsA 

microemulsion: 

German study 

and suspension 

trial Methylpred. 

German study 

Prednisone 

suspension trial 

corticosteroids 

Form 

measured: 

MPA German 

study and 

suspension trial 

MPAG 

suspension trial 

Method of 

measurement: 

 suspension trial 

Frequency of 

MPA measure: 

german study: 

day 7 and 21 

post transplant 

(initial phase) 

and 3 and 6m 

post transplant 

(stable phase) 

suspension trial: 

day 7 and month 

3, 9, 24, and 36 

Assay used: 

HPLC German 

study 

EMIT German 

study 

LC-MS 

suspension trial 

Health 

outcome: 

acute 

rejection 

side effects 

such as 

leukopenia 

and 

infections 

Length of 

followup: 

German 

study: 6m 

post 

transplant 

suspension 

trial: 36m 
C-45

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Weber 

Year: 

2002 

Country: 

Germany 

Aim: 

To determine the 

utility of the EMIT 

assay compared to 

the HPLC in 

identifying pediatric 

renal transplant 

patients at risk for 

acute graft rejection. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

50 

Analyzed: 

50 

Population: 

all Caucasian 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 11.8y 

Range 3.2 - 16.0y 

% Male: 62 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 600 mg/m2 

BID to a 

maximum of 2 

g/day 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Cyclosporine 

Methylpred. 

Form 

measured: 

MPA 

Method of 

measurement: 

Co 

Cmax 

AUC0-12

AUC0-2

Frequency of 

MPA measure: 

on day 7 and 21 

posttransplant 

('initial phase') 

and 3 and 6 

months post 

transplant 

('stable phase') 

Assay used: 

HPLC 

EMIT 

Health 

outcome: 

acute 

rejection 

leukopenia 

diarrhea 

anemia 

Length of 

followup: 

6m 

Author: 

Weber 

Year: 

2001 

Country: 

Germany 

Aim: 

To determine the 

PK-pharmodynamic 

realtionship for MPA 

in pediatric renal 

transplant patients. 

Comparison of 

monitored patients 

with others: No 

Study design: Case 

series 

Entered into study: 

54 

Analyzed: 

54 

Population: 

All patients were 

caucasian. 

Organ

transplanted: 

Kidney (Renal) 

Age: Inclusion 

requirement 

described in study 

refid 13563, 

13860 

Range 2.2 - 17.8y 

% Male: 61.1 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 600 mg/m2 

BSA twice a day 

up to 2 g/day max 

Prospective

dose adjustment

planned: Yes - 

based on clinical 

indicators 

Concomitant

medications: 

Cyclosporine 

Methylpred. 

Form 

measured: 

MPA 

Method of 

measurement: 

Predose 

concentration 0 - 

2 hour 

Predose 

concentration 

time to 

maximum 

concentration 

Frequency of 

MPA measure: 

7 and 21 days 

post transplant 

(initial phase), 3 

and 6 months 

posttransplant 

(stable phase) 

Assay used: 

Not reported 

described in 

other studies 

refid 13860, 

13867 

Health 

outcome: 

acute 

rejection 

leukopenia 

infections 

Length of 

followup: 

6m 
C-46

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Weber 

Year: 

1999 

Country: 

Germany 

Aim: 

A sequential 

investigation of MPA 

PK in initial and 

stable phase in 

pediatric renal 

transplantat 

recipients. 

Comparison of 

monitored patients 

with others: No 

Study design: Case 

series 

Entered into study: 

17 

Analyzed: 

17 

Population: 

pediatric renal 

transplant 

patients 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 12.0 +/- 

0.8y 

Range 5.9-15.8y 

% Male: 53 

Weight: 

Mean 37.6 +/- 3.3 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 600 mg/m2 

BSA BID to max 

of 2g/day 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Methylpred. 

Form 

measured: 

MPA 

MPAG 

fMPA 

Method of 

measurement: 

AUC(0-12h)

Tmax

Cmax

Cmin

Frequency of 

MPA measure: 

day 7, 21 = 

initial phase, 3, 

6 months = 

stable phase 

Assay used: 

HPLC 

Health 

outcome: 

GFR 

Length of 

followup: 

6m 

Author: 

Weber 

Year: 

1998 

Country: 

Germany 

Aim: 

Evaluation of the PK 

of MPA in Renal 

transplant patients. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case control 

Entered into study: 

Condition 1 children 

n=18 

Condition 2 adults 

n=10 

Analyzed: 

Condition 1 children 

n=18 

Condition 2 adults 

n=10 

Population: 

patients receiving 

first or second 

renal transplant 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean children 

10.7 +/- 0.72; 

adults 45.9 +/- 4.1 

Range for entire 

population 

children 5.9 - 

15.3; adults 20.1 - 

59.2 

% Male: 64% 

(adults and 

children) 

Weight: 

Mean children: 

weight 29.3 +/- 

2.49 kg; BSA 1.02 

+/- 0.06 m 

(squared). adults: 

weight 78.7 +/- 

3.2 kg; BSA 1.93 

+/- 0.04 m 

(squared) 

Range: Children 

16-50.3; adults 

65.8-98.4 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: Children: 

600 mg/m2 body 

surface area BID 

Adults: 1 g BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

cyclosporin A 

Methylpred. 

Form 

measured: 

MPA 

MPAG 

free MPA 

Method of 

measurement: 

mimimum 

concentration 

MPA-AUC(0-12h)

Frequency of 

MPA measure: 

day 7 and day 

21 

Assay used: 

HPLC reverse 

phase 

Health 

outcome: 

transplant 

dysfunction 

decreased 

albumin 

levels 

GFR in 

children 

creatinine 

clearance 

rate in 

adults 

Length of 

followup: 

3w 
C-47

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Wolfe 

Year: 

1995 

Country: 

USA 

Aim: 

PK of MMF and IV 

Ganciclovir alone 

and in combination in 

Renal transplant 

recipients 

Comparison of 

monitored patients 

with others: No 

Study design: 

RCT 

Entered into study: 

12 

Analyzed: 

12 

Population: 

recent kidney 

transplant with 

stable renal 

functions 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 36 +/- 13y 

Range 20-57y 

% Male: 100% 

Weight: 

Mean 79 +/- 19; 

lean body weight 

69.0 +/- 7.5 

Range 56.9-79.9 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: single dose 

of 1500 mg in 

each of two 

treatment arms; 

one arm alone 

and one arm 

combined with 

ganciclovir 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Ganciclovir in 2 

arms, one arm 

alone and 1 arm 

combined with 

MMF 

Azathioprine 

Form 

measured: 

MPA 

MPAG 

Method of 

measurement: 

 time to peak 

concentration 

 area under the 

concentration 

time curve 

 apparent 

volume of 

distributionoral 

plasma 

clearancerenal 

clearance half 

lifebl 

Frequency of 

MPA measure: 

blood: before 

and 12 times in 

48 h after 

dosing. Urine: 

48 hour 

monitoring 

Assay used: 

HPLC-UV 

Health 

outcome: 

potential 

drug 

interaction 

between 

MPA and 

ganciclovir 

creatinine 

clearance 

Length of 

followup: 

3w 

Author: 

Wollenberg 

Year: 

1998 

Country: 

Germany 

Aim: 

to determine PK data 

of MPA during 

different periods after 

transplant. 

Comparison of 

monitored patients 

with others: No 

Study design: 

Non-randomized 

Controlled Trial 

Entered into study: 

Condition 1 24 

Condition 2 24 

Analyzed: 

Condition 1 24 

Condition 2 24 

Population: 

enrolled after 

renal 

transplantation 

Organ

transplanted: 

Kidney (Renal) 

Age: 

Mean 48 +/- 15y 

% Male: 81 

Weight: 

Mean BMI 24.4 

+/- 2.4 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1 g BID 

Prospective

dose adjustment

planned: No 

Concomitant

medications: 

Cyclosporine 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

 trough 

Frequency of 

MPA measure: 

after MMF dose: 

0.5,1,2,4,6,8 

and 12 h 

Assay used: 

EMIT 

Health 

outcome: 

creatinine 

Length of 

followup: 

>3m 
C-48

Evidence Table 1. General information for all included studies (continued) 

Study ID Study Description Population Treatment Measures Outcomes 

Author: 

Yamani 

Year: 

2000 

Country: 

USA 

Aim: 

Evaluate the 

incidence of rejection 

in relation to MMF 

trough level following 

heart transplantation 

Comparison of 

monitored patients 

with others: No 

Study design: 

Retrospective Cohort 

Entered into study: 

215 

Analyzed: 

215 

Population: 

Heart tx patients 

Organ

transplanted: 

Heart (Cardiac) 

Age: 

Range 36 +/- 14y 

% Male: 81 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 2 g/day 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Prednisone 

Form 

measured: 

MPA 

Method of 

measurement: 

 trough 

Frequency of 

MPA measure: 

12m 

Assay used: 

EMIT 

Health 

outcome: 

rejection VS 

trough 

rejection VS 

CSA/Tac 

levels VS 

MPA levels 

WBC - 

lymphocyte 

(total 

percent) 

Length of 

followup: 

179 +/- 52d 

Author: 

Zakliczynski 

Year: 

2005 

Country: 

Poland 

Aim: 

To assess clinical 

utility of MPA trough 

concentration 

monitoring in heart 

transplant patients 

Comparison of 

monitored patients 

with others: No 

Study design: 

Case series 

Entered into study: 

76 

Analyzed: 

76 

Population: 

Post heart tx 

patients 

Organ

transplanted: 

Heart (Cardiac) 

Age: 

Mean 41.9 +/- 16y 

% Male: 75 

Weight: 

NR 

 

Form given: 

Mycophenolate 

mofetil (MMF, 

CellCept) 

Dose: 1g BID, 1.5 

g BID for adjusted 

>90kg 

Prospective

dose adjustment

planned: Yes - 

based on MPA (or 

metabolite) blood 

levels 

Concomitant

medications: 

Cyclosporine 

Tacrolimus 

Prednisone 

Azathioprine 

Form 

measured: 

MPA 

Method of 

measurement: 

 trough levels 

Frequency of 

MPA measure: 

NR 

Assay used: 

EMIT 

Health 

outcome: 

GI 

symptoms 

leucopenia 

anemia 

Length of 

followup: 

NR 
C-49

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83. 

Kreis H, Cisterne JM, Land W, et al. Sirolimus in 

association with mycophenolate mofetil induction for the 

prevention of acute graft rejection in renal allograft 

recipients. Transplantation 2000;69(7):1252-60. 

Krumme B, Wollenberg K, Kirste G, et al. Drug monitoring 

of mycophenolic acid in the early period after renal 

transplantation. Transplant Proc 1998;30(5):1773-4. 

Kuriata-Kordek M, Boratynska M, Klinger M, et al. The 

efficacy of mycophenolate mofetil treatment in the 

prevention of acute renal rejection is related to plasma level 

of mycophenolic acid. Transplant Proc 2002;34(7):2985-7. 

Kuypers DR, Vanrenterghem Y, Squifflet JP, et al. Twelvemonth evaluation of the clinical pharmacokinetics of total 

and free mycophenolic acid and its glucuronide metabolites 

in renal allograft recipients on low dose tacrolimus in 

combination with mycophenolate mofetil. Ther Drug Monit 

2003b;25(5):609-22. 

Kuypers DR, Claes K, Evenepoel P, et al. Long-term 

changes in mycophenolic acid exposure in combination with 

tacrolimus and corticosteroids are dose dependent and not 

reflected by trough plasma concentration: a prospective study 

in 100 de novo renal allograft recipients. J Clin Pharmacol 

2003a;43(8):866-80. 

Kuypers DR, Claes K, Evenepoel P, et al. Clinical efficacy 

and toxicity profile of tacrolimus and mycophenolic acid in 

relation to combined long-term pharmacokinetics in de novo 

renal allograft recipients. Clin Pharmacol Ther 

2004;75(5):434-47. 

Le Meur Y, Buchler M, Thierry A, et al. Individualized 

mycophenolate mofetil dosing based on drug exposure 

significantly improves patient outcomes after renal 

transplantation. Am J Transplant 2007;7(11):2496-503. 

Lu XY, Huang HF, Sheng-Tu JZ, et al. Pharmacokinetics of 

mycophenolic acid in Chinese kidney transplant patients. J 

Zhejiang Univ 2005;Science B(9):885-91. 

Lu YP, Lin B, Liang MZ, et al. Correlation of mycophenolic 

acid pharmacokinetic parameters with side effects in Chinese 

kidney transplant recipients treated with mycophenolate 

mofetil. Transplant Proc 2004;36(7):2079-81. 

Lu YP, Zhu YC, Liang MZ, et al. Therapeutic Drug 

Monitoring of Mycophenolic Acid Can Be Used as Predictor 

of Clinical Events for Kidney Transplant Recipients Treated 

With Mycophenolate Mofetil. Transplant Proc 

2006;38(7):2048-50. 

Maes BD, Dalle I, Geboes K, et al. Erosive enterocolitis in 

mycophenolate mofetil-treated renal-transplant recipients 

with persistent afebrile diarrhea. Transplantation 

2003;75(5):665-72. 

Mandla R, Midtvedt K, Line PD, et al. Mycophenolic acid 

clinical pharmacokinetics influenced by a cyclosporine C2 

based immunosuppressive regimen in renal allograft 

recipients. Transpl Int 2006;19(1):44-53. 

Meiser BM, Pfeiffer M, Schmidt D, et al. The efficacy of the 

combination of tacrolimus and mycophenolate mofetil for 

prevention of acute myocardial rejection is dependent on 

routine monitoring of mycophenolic acid trough acid levels. 

Transplant Proc 1999a;31(1-2):84-7. 

Meiser BM, Pfeiffer M, Schmidt D, et al. Combination 

therapy with tacrolimus and mycophenolate mofetil 

following cardiac transplantation: importance of 

mycophenolic acid therapeutic drug monitoring. J Heart 

Lung Transplant 1999b;18(2):143-9. 

Merkel U, Lindner S, Vollandt R, et al. Trough levels of 

mycophenolic acid and its glucuronidated metabolite in renal 

transplant recipients. Int J Clin Pharmacol Ther 

2005;43(8):379-88. 

Morgera S, Neumayer HH, Fritsche L, et al. 

Pharmacokinetics of mycophenolate mofetil in renal 

transplant recipients on peritoneal dialysis. Int J Clin 

Pharmacol Ther 1998b;36(3):159-63. 
C-51

Morgera S, Budde K, Lampe D, et al. Mycophenolate 

mofetil pharmacokinetics in renal transplant recipients on 

peritoneal dialysis. Transpl Int 1998a;11(1):53-7. 

Mourad M, Chaib-Eddour D, Malaise J, et al. Analytical and 

clinical evaluation of the EMIT mycophenolic acid 

immunoassay in kidney transplantation. Transplant Proc 

2000;32(2):404-6. 

Mourad M, Malaise J, Chaib ED, et al. Pharmacokinetic 

basis for the efficient and safe use of low-dose 

mycophenolate mofetil in combination with tacrolimus in 

kidney transplantation. Clin Chem 2001b;47(7):1241-8. 

Mourad M, Malaise J, Chaib ED, et al. Correlation of 

mycophenolic acid pharmacokinetic parameters with side 

effects in kidney transplant patients treated with 

mycophenolate mofetil. Clin Chem 2001a;47(1):88-94. 

Mudge DW, Atcheson B, Taylor PJ, et al. The effect of oral 

iron admiinistration on mycophenolate mofetil absorption in 

renal transplant recipients: a randomized, controlled trial. 

Transplantation 2004;77(2):206-9. 

Naesens M, Kuypers DRJ, Verbeke K, et al. Multidrug 

resistance protein 2 genetic polymorphisms influence 

mycophenolic acid exposure in renal allograft recipients. 

Transplantation 2006;82(8):1074-84. 

Naito T, Shinno K, Maeda T, et al. Effects of calcineurin 

inhibitors on pharmacokinetics of mycophenolic acid and its 

glucuronide metabolite during the maintenance period 

following renal transplantation. Biol Pharm Bull 

2006;29(2):275-80. 

Okamoto M, Wakabayashi Y, Higuchi A, et al. Therapeutic 

drug monitoring of mycophenolic acid in renal transplant 

recipients. Transplant Proc 2005;37(2):859-60. 

Orlando G, Baiocchi L, Cardillo A, et al. Switch to 1.5 

grams MMF monotherapy for CNI-related toxicity in liver 

transplantation is safe and improves renal function, 

dyslipidemia, and hypertension. Liver Transpl 

2007;13(1):46-54. 

Pape L, Ehrich JH, Offner G. Long-term follow-up of 

pediatric transplant recipients: mycophenolic acid trough 

levels are not a good indicator for long-term graft function. 

Clin Transplant 2004;18(5):576-9. 

Pawinski T, Durlik M, Szlaska I, et al. Comparison of 

mycophenolic acid pharmacokinetic parameters in kidney 

transplant patients within the first 3 months post-transplant. 

J Clin Pharm Ther 2006b;31(1):27-34. 

Pawinski T, Durlik M, Szlaska I, et al. The weight of 

pharmacokinetic parameters for mycophenolic acid in 

prediction of rejection outcome: the receiver operating 

characteristic curve analysis. Transplant Proc 

2006a;38(1):86-9. 

Pillans PI, Rigby RJ, Kubler P, et al. A retrospective 

analysis of mycophenolic acid and cyclosporin 

concentrations with acute rejection in renal transplant 

recipients. Clin Biochem 2001;34(1):77-81. 

Reggiani P, Arru M, Regazzi M, et al. A "steroid-free" 

tacrolimus and low-dose mycophenolate mofetil primary 

immunosuppression does not prevent early acute rejection 

after liver transplantation. Transplant Proc 2005;37(4):1697-

9. 

Ringe B, Braun F, Schutz E, et al. A novel management 

strategy of steroid-free immunosuppression after liver 

transplantation: efficacy and safety of tacrolimus and 

mycophenolate mofetil. Transplantation 2001;71(4):508-15. 

Satoh S, Tada H, Murakami M, et al. The influence of 

mycophenolate mofetil versus azathioprine and 

mycophenolic acid pharmacokinetics on the incidence of 

acute rejection and infectious complications after renal 

transplantation. Transplant Proc 2005;37(4):1751-3. 

Satoh S, Tada H, Murakami M, et al. Circadian 

pharmacokinetics of mycophenolic Acid and implication of 

genetic polymorphisms for early clinical events in renal 

transplant recipients. Transplantation 2006;82(4):486-93. 

Shaw LM, Mick R, Nowak I, et al. Pharmacokinetics of 

mycophenolic acid in renal transplant patients with delayed 

graft function. J Clin Pharmacol 1998;38(3):268-75. 

Shaw LM, Korecka M, Aradhye S, et al. Mycophenolic acid 

area under the curve values in African American and 

Caucasian renal transplant patients are comparable. J Clin 

Pharmacol 2000;40(6):624-33. 

Smak Gregoor PJ, Hesse CJ, van Gelder T, et al. Relation of 

mycophenolic acid trough levels and adverse events in 

kidney allograft recipients. Transplant Proc 

1998;30(4):1192-3. 

Smak Gregoor PJ, van Gelder T, van Besouw NM, et al. 

Randomized study on the conversion of treatment with 

cyclosporine to azathioprine or mycophenolate mofetil 

followed by dose reduction. Transplantation 

2000b;70(1):143-8. 

Smak Gregoor PJ, van Gelder T, van Besouw NM, et al. 

Mycophenolic acid trough levels after kidney transplantation 

in a cyclosporine-free protocol. Transpl Int 2000a;13(Suppl 

1):S333-S335 

Sugioka N, Sasaki T, Kokuhu T, et al. Clinical 

pharmacokinetics of mycophenolate mofetil in Japanese 

renal transplant recipients: A retrospective cohort study in a 

single center. Biol Pharm Bull 2006;29(10):2099-105. 

Sumethkul V, Na-Bangchang K, Kantachuvesiri S, et al. 

Standard dose enteric-coated mycophenolate sodium 

(myfortic) delivers rapid therapeutic mycophenolic acid 

exposure in kidney transplant recipients. Transplant Proc 

2005;37(2):861-3. 
C-52

Takahashi K, Ochiai T, Uchida K, et al. Pilot study of 

mycophenolate mofetil (RS-61443) in the prevention of 

acute rejection following renal transplantation in Japanese 

patients. RS-61443 Investigation Committee--Japan. 

Transplant Proc 1995;27(1):1421-4. 

Tredger JM, Brown NW, Adams J, et al. Monitoring 

mycophenolate in liver transplant recipients: toward a 

therapeutic range. Liver Transpl 2004;10(4):492-502. 

Tsaroucha AK, Zucker K, Esquenazi V, et al. Levels of 

mycophenolic acid and its glucuronide derivative in the 

plasma of liver, small bowel and kidney transplant patients 

receiving tacrolimus and cellcept combination therapy. 

Transpl Immunol 2000;8(2):143-6. 

van Besouw NM, Van Der Mast BJ, Smak Gregoor PJ, et al. 

Effect of mycophenolate mofetil on erythropoiesis in stable 

renal transplant patients is correlated with mycophenolic acid 

trough levels. Nephrol Dial Transplant 1999;14(11):2710-3. 

van Gelder T, Hilbrands LB, Vanrenterghem Y, et al. A 

randomized double-blind, multicenter plasma concentration 

controlled study of the safety and efficacy of oral 

mycophenolate mofetil for the prevention of acute rejection 

after kidney transplantation. Transplantation 

1999;68(2):261-6. 

Wang CX, Meng FH, Chen LZ, et al. Population 

Pharmacokinetics of Mycophenolic Acid in Senile Chinese 

Kidney Transplant Recipients. Transplant Proc 

2007;39(5):1392-5. 

Wang X, Tang X, Xu D. Immunosuppressive effect of 

mycophenolate mofetil with two different dosages in 

cadaveric renal transplantation: a short study. Transplant 

Proc 1998;30(7):3573-4. 

Weber LT, Shipkova M, Lamersdorf T, et al. 

Pharmacokinetics of mycophenolic acid (MPA) and 

determinants of MPA free fraction in pediatric and adult 

renal transplant recipients. German Study group on 

Mycophenolate Mofetil Therapy in Pediatric Renal 

Transplant Recipients. J Am Soc Nephrol 1998;9(8):1511-

20. 

Weber LT, Lamersdorf T, Shipkova M, et al. Area under the 

plasma concentration-time curve for total, but not for free, 

mycophenolic acid increases in the stable phase after renal 

transplantation: a longitudinal study in pediatric patients. 

German Study Group on Mycophenolate Mofetil Therapy in 

Pediatric Renal Transplant Recipients. Ther Drug Monit 

1999;21(5):498-506. 

Weber LT, Shipkova M, Armstrong VW, et al. The 

pharmacokinetic-pharmacodynamic relationship for total and 

free mycophenolic Acid in pediatric renal transplant 

recipients: a report of the german study group on 

mycophenolate mofetil therapy. J Am Soc Nephrol 

2002;13(3):759-68. 

Weber LT, Shipkova M, Armstrong VW, et al. Comparison 

of the Emit immunoassay with HPLC for therapeutic drug 

monitoring of mycophenolic acid in pediatric renal-transplant 

recipients on mycophenolate mofetil therapy. Clin Chem 

2002;48(3):517-25. 

Weber LT, Hoecker B, Armstrong VW, et al. Validation of 

an abbreviated pharmacokinetic profile for the estimation of 

mycophenolic acid exposure in pediatric renal transplant 

recipients. Ther Drug Monit 2006;28(5):623-31. 

Wolfe EJ, Mathur V, Tomlanovich S, et al. 

Pharmacokinetics of mycophenolate mofetil and intravenous 

ganciclovir alone and in combination in renal transplant 

recipients. Pharmacotherapy 1997;17(3):591-8. 

Wollenberg K, Krumme B, Schollmeyer P, et al. 

Pharmacokinetics of mycophenolic acid after renal 

transplantation. Transplant Proc 1998;30(5):2237-9. 

Yamani MH, Starling RC, Goormastic M, et al. The impact 

of routine mycophenolate mofetil drug monitoring on the 

treatment of cardiac allograft rejection. Transplantation 

2000;69(11):2326-30. 

Zakliczynski M, Szewczyk M, Zakliczynska H, et al. 

Clinical application of monitoring mycophenolic acid trough 

concentration in heart transplant recipients--single center's 

experience. Ann Transplant 2005;10(2):38-45. 
D-1

Appendix D. List of Excluded Studies 

CellCept shown to improve 3-year graft survival in renal 

transplantation. Dialysis & Transplantation 1997;26(8):523 

Excluded because not a full report of an included study 

type 

Aigrain EJ, Shaghaghi EK, Baudouin V, et al. 

Pharmacokinetics of mycophenolate mofetil in eight 

pediatric renal transplant patients. Transplant Proc 

2000;32(2):388-90. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Akhlaghi F, Patel CG, Zuniga XP, et al. Pharmacokinetics 

of mycophenolic acid and metabolites in diabetic kidney 

transplant recipients. Ther Drug Monit 2006;28(1):95-101. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Akoglu B, Wondra K, Caspary WF, et al. Determinants of 

fasting total serum homocysteine levels in liver transplant 

recipients. Exp Clin Transplant 2006;4(1):462-6. 

Excluded because MPA not measured in blood 

Al Aly Z, Sachdeva A, Philoctete Ashley JM, et al. 

Preliminary experience with mycophenolate mofetil for 

preservation of renal function in cardiac transplant patients 

with documented cyclosporine nephrotoxicity. Nephrology 

2006;11(2):151-5. 

Excluded because not a full report of an included study 

type 

Al Khoury S, Shah N, Afzali B, et al. Post-transplantation 

anaemia in adult and paediatric renal allograft recipients - 

Guy's Hospital experience. Nephrol Dial Transplant 

2006;21(7):1974-80. 

Excluded because MPA not measured in blood 

Anil Kumar MS, Moritz MJ, Saaed MI, et al. Avoidance of 

chronic steroid therapy in African American kidney 

transplant recipients monitored by surveillance biopsy: 1-

year results. Am J Transplant 2005;5(8):1976-85. 

Excluded because MPA not measured in blood 

Annesley TM, Clayton LT. Quantification of mycophenolic 

acid and glucuronide metabolite in human serum by HPLCtandem mass spectrometry. Clin Chem 2005;51(5):872-7. 

Excluded because not a full report of an included study 

type 

Arbogast H, Huckelheim H, Schneeberger H, et al. A 

calcineurin antagonist-free induction/maintenance strategy 

for immunosuppression in elderly recipients of renal 

allografts from elderly cadaver donors: long-term results 

from a prospective single centre trial. Clin Transplant 

2005;19(3):309-15. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Armstrong VW, Tenderich G, Shipkova M, et al. 

Pharmacokinetics and bioavailability of mycophenolic acid 

after intravenous administration and oral administration of 

mycophenolate mofetil to heart transplant recipients. Ther 

Drug Monit 2005;27(3):315-21. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Arns W, Breuer S, Choudhury S, et al. Enteric-coated 

mycophenolate sodium delivers bioequivalent MPA 

exposure compared with mycophenolate mofetil. Clin 

Transplant 2005;19(2):199-206. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Arns W, Gies M, Choi L, et al. Absorption characteristics 

of EC-MPS - An enteric-coated formulation of 

mycophenolic sodium. Int J Clin Pharmacol Ther 

2006;44(8):375-85. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Atcheson BA, Taylor PJ, Kirkpatrick CM, et al. Free 

mycophenolic acid should be monitored in renal transplant 

recipients with hypoalbuminemia. Ther Drug Monit 

2004;26(3):284-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Au WY, Lie AK, Cheng VCC, et al. Successful Lung 

Transplantation for Post-BMT Bronchiolitis Obliterans and 

Lipoid Pneumonia Associated with Atypical 

Mycobacterium and Aspergillosis Infection. J Heart Lung 

Transplant 2007;26(8):870-2. 

Excluded because not a full report of an included study 

type 

Augustine JJ, Knauss TC, Schulak JA, et al. Comparative 

effects of sirolimus and mycophenolate mofetil on 

erythropoiesis in kidney transplant patients. Am J 

Transplant 2004;4(12):2001-6. 

Excluded because MPA not measured in blood 

Aumente R, Arizon Del Prado JM, Lopez Malo De Molina 

MD, et al. Clinical pharmacokinetics of tacrolimus in heart 

transplantation: new strategies of monitoring. Transplant 

Proc 2003;35(5):1988-91. 

Excluded because MPA not measured in blood 

Aw MM, Brown NW, Itsuka T, et al. Mycophenolic acid 

pharmacokinetics in pediatric liver transplant recipients. 

Liver Transplantation 2003;9(4):383-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Balbontin FG, Kiberd B, Squires J, et al. Tacrolimus 

monitoring by simplified sparse sampling under the 

concentration time curve. Transplant Proc 

2003;35(7):2445-8. 
D-2

Excluded because MPA not measured in blood 

Baraldo M, Isola M, Feruglio MT, et al. Therapeutic 

mycophenolic acid monitoring by means of limited 

sampling strategy in orthotopic heart transplant patients. 

Transplant Proc 2005;37(5):2240-3. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Barcena R, Oton E, Barreales M, et al. Scarce Influence of 

Corticosteroid Boluses on Long-Term Viral Load and Liver 

Histology in Transplanted Patients With Recurrent 

Hepatitis C. Transplant Proc 2006;38(8):2502-4. 

Excluded because MPA not measured in blood 

Barten MJ, Rahmel A, Chang H, et al. Assessment of 

immunosuppression by lymphocyte functions in human 

blood. Transplant Proc 2002;34(7):2876-7. 

Excluded because does not report on humans with a solid 

organ transplant 

Barten MJ, Rahmel A, Garbade J, et al. Pharmacodynamic 

monitoring of the conversion of cyclosporine to tacrolimus 

in heart and lung transplant recipients. Transplant Proc 

2005;37(10):4532-4. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Barten MJ, Rahmel A, Garbade J, et al. C0h/C2h 

monitoring of the pharmacodynamics of cyclosporin plus 

mycophenolate mofetil in human heart transplant 

recipients. Transplant 

Proc 2005;37(2):1360-1. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Barton TD, Blumberg EA, Doyle A, et al. A prospective 

cross-sectional study of BK virus infection in non-renal 

solid organ transplant recipients with chronic renal 

dysfunction. Transplant Infectious Disease 2006;8(2):102-

7. 

Excluded because MPA not measured in blood 

Beaulieu AJ, Lapane KL, Gohh RY, et al. Short-term 

reproducibility of total homocysteine determinations in 

stable renal transplant recipients. Transplant Proc 

1999;31(5):2121-3. 

Excluded because MPA not measured in blood 

Beaunoyer M, Busque S, St Louis G, et al. Low-dose 

tacrolimus, trough-monitored mycophenolate mofetil, and 

planned steroid withdrawal for cadaveric kidney 

transplantation: a single center experience. Transplant Proc 

2002;34(5):1694-5. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Belev B, Simeonov P, Popov R, et al. First observations in 

our country on the administration of mycophenolate 

mofetill (cellcept) in patients with translplanted kidney. 

Nephrolgy, Hemodialysis, Transplantation 1999;5(1):45-6. 

Excluded because not published in English 

Benech H, Hascoet S, Furlan V, et al. Development and 

validation of an LC/MS/MS assay for mycophenolic acid in 

human peripheral blood mononuclear cells. J Chromatogr 

B: Analyt Technol Biomed Life Sci 2007;853(1-2):168-74. 

Excluded because not a full report of an included study 

type 

Berger N, Guggenbichler S, Steurer W, et al. Bloodstream 

infection following 217 consecutive systemic-enteric 

drained pancreas transplants. BMC Infect Dis 2006;6:127 

Excluded because MPA not measured in blood 

Bestetti RB, Souza TR, Lima MF, et al. Effects of a 

mycophenolate mofetil-based immunosuppressive regimen 

in Chagas' heart transplant recipients [2]. Transplantation 

2007;84(3):441-2. 

Excluded because MPA not measured in blood 

Bestetti RB, Souza TR, Lima MF, et al. Effects of a 

mycophenolate mofetil-based immunosuppressive regimen 

in Chagas' heart transplant recipients. Transplantation 

2007;84(3):441-2. 

Excluded because not a full report of an included study 

type 

Bogusz MJ, Enazi EA, Hassan H, et al. Simultaneous LCMS-MS determination of cyclosporine A, tacrolimus, and 

sirolimus in whole blood as well as mycophenolic acid in 

plasma using common pretreatment procedure. J 

Chromatogr B Analyt Technol Biomed Life Sci 

2007;850(1-2):471-80. 

Excluded because does not report on humans with a solid 

organ transplant 

Bohler T, Nolting J, Kamar N, et al. Validation of 

immunological biomarkers for the pharmacodynamic 

monitoring of immunosuppressive drugs in humans. Ther 

Drug Monit 2007;29(1):77-86. 

Excluded because MPA not measured in blood 

Boldt A, Barten MJ, Sagner A, et al. The influence of 

immunosuppressive drugs on T- and B-cell apoptosis via 

p53-mediated pathway in vitro and in vivo. 

Transplantation 2006;82(3):422-7. 

Excluded because MPA not measured in blood 

Borrows R, Chusney G, Loucaidou M, et al. Clinical 

outcomes of renal transplantation using liquid 

chromatographic monitoring of tacrolimus. Ther Drug 

Monit 2006;28(2):269-73. 

Excluded because MPA not measured in blood 

Borrows R, Chusney G, Loucaidou M, et al. The 

magnitude and time course of changes in 

mycophenolic acid 12-hour predose levels during antibiotic 

therapy in mycophenolate mofetil-based renal 

transplantation. Ther Drug Monit 2007;29(1):122-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 
D-3

Borrows R, Chusney G, Loucaidou M, et al. Analysis of 

factors influencing tacrolimus levels and immunoassay bias 

in renal transplantation. J Clin Pharmacol 

2007;47(8):1035-42. 

Excluded because MPA not measured in blood 

Bravo Soto JA, Esteban De La Rosa RJ, Luna Del Castillo 

JD, et al. Effect of mycophenolate mofetil regimen on 

peripheral blood lymphocyte subsets in kidney transplant 

recipients. Transplant Proc 2003;35(4):1355-9. 

Excluded because MPA not measured in blood 

Broeders N, Wissing KM, Crusiaux A, et al. 

Mycophenolate mofetil, together with cyclosporin A, 

prevents anti-OKT3 antibody response in kidney transplant 

recipients. J Am Soc Nephrol 1998;9(8):1521-5. 

Excluded because MPA not measured in blood 

Brown NW, Aw MM, Mieli-Vergani G, et al. 

Mycophenolic acid and mycophenolic acid 

glucuronide pharmacokinetics in pediatric liver transplant 

recipients: effect of cyclosporine and tacrolimus 

comedication. Ther Drug Monit 2002;24(5):598-606. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Brunet M, Oppenheimer F, Martorell J, et al. 

Mycophenolic acid monitoring: evaluation of the EMIT 

MPA immunoassay in kidney and lung transplantation. 

Transplant Proc 1999;31(6):2275-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Brunet M, Millan O, Jimenez O, et al. New concepts in 

cyclosporine pharmacokinetic and dynamic monitoring: the 

impact of concomitant immunosuppression on target C2 

concentrations. Transplant Proc 2004;36(2:Suppl):Suppl441S 

Excluded because MPA levels not associated with any 

clinical outcomes 

Brunet M, Crespo M, Millan O, et al. Pharmacokinetics 

and pharmacodynamics in renal transplant recipients under 

treatment with cyclosporine and myfortic. Transplant Proc 

2007;39(7):2160-2. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Buchler M, Lebranchu Y, Beneton M, et al. Higher 

exposure to mycophenolic acid with sirolimus than with 

cyclosporine cotreatment. Clin Pharmacol Ther 

2005;78(1):34-42. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Budde K, Braun KP, Glander P, et al. Pharmacodynamic 

monitoring of mycophenolate mofetil in stable renal 

allograft recipients. Transplant Proc 2002;34(5):1748-50. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Budde K, Knoll G, Curtis J, et al. Safety and efficacy after 

conversion from mycophenolate mofetil to enteric-coated 

mycophenolate sodium: results of a 1-year extension study. 

Transplant Proc 2005;37(2):912-5. 

Excluded because MPA not measured in blood 

Budde K, Knoll G, Curtis J, et al. Long-term safety and 

efficacy after conversion of maintenance renal transplant 

recipients from mycophenolate mofetil (MMF) to entericcoated mycophenolate sodium (EC-MPA, myfortic). Clin 

Nephrol 2006;66(2):103-11. 

Excluded because MPA not measured in blood 

Budde K, Glander P, Kramer BK, et al. Conversion from 

mycophenolate mofetil to enteric-coated mycophenolate 

sodium in maintenance renal transplant recipients receiving 

tacrolimus: clinical, pharmacokinetic, and 

pharmacodynamic outcomes. Transplantation 2007;83(4): 

417-24. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Budde K, Bauer S, Hambach P. Erratum: Pharmacokinetic 

and pharmacodynamic comparison of enteric-coated 

mycophenolate sodium and mycophenolate mofetil in 

maintenance renal transplant patients (Am J Transplant 7, 

4, (888-898) DOI:10.1111/j.1600-6143.2007.01693.x). 

Am J Transplant 2007;(8):2057 

Excluded because not a full report of an included study 

type 

Budde K, Tedesco-Silva H, Pestana JM, et al. Entericcoated mycophenolate sodium provides higher 

mycophenolic acid predose levels compared with 

mycophenolate mofetil: implications for therapeutic drug 

monitoring. Ther Drug Monit 2007;29(3):381-4. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Budde K, Bauer S, Hambach P, et al. Pharmacokinetic and 

pharmacodynamic comparison of enteric-coated 

mycophenolate sodium and mycophenolate mofetil in 

maintenance renal transplant patients. Am J Transplant 

2007;7(4):888-98. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Bullingham R, Monroe S, Nicholls A, et al. 

Pharmacokinetics and bioavailability of mycophenolate 

mofetil in healthy subjects after single-dose oral and 

intravenous administration. J Clin Pharmacol 

1996;36(4):315-24. 

Excluded because does not report on humans with a solid 

organ transplant 

Bunnapradist S, Danovitch GM. Minimizing ciclosporin in 

renal transplant recipients on daclizumab, mycophenolate 

and steroids. Nature Clinical Practice Nephrology 

2007;3(8):426-7. 

Excluded because not a full report of an included study 

type 
D-4

Butcher JA, Hariharan S, Adams MB, et al. Renal 

transplantation for end-stage renal disease following bone 

marrow transplantation: A report of six cases, with and 

without immunosuppression. Clin Transplant 

1999;13(4):330-5. 

Excluded because not a full report of an included study 

type 

Calvo N, Sanchez-Fructuoso AI, Conesa J, et al. Renal 

Transplant Patients With Gastrointestinal Intolerability to 

Mycophenolate Mofetil: Conversion to Enteric-Coated 

Mycophenolate Sodium. Transplant Proc 2006;38(8):2396-

7. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Cantarovich M, Giannetti N, Cecere R. Impact of 

cyclosporine 2-h level and mycophenolate mofetil dose on 

clinical outcomes in de novo heart transplant patients 

receiving anti-thymocyte globulin induction. Clin 

Transplant 2003;17(2):144-50. 

Excluded because MPA not measured in blood 

Casas RV, Lopez AV, Rey JLN, et al. Mycophenolic Acid 

Reaches Therapeutic Levels Whereas Mycophenolate 

Mofetil Does Not. Transplant Proc 2006;38(8):2400-1. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Cattaneo D, Perico N, Gaspari F, et al. Glucocorticoids 

interfere with mycophenolate mofetil bioavailability in 

kidney transplantation. Kidney Int 2002;62(3):1060-7. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Cattaneo D, Merlini S, Pellegrino M, et al. Therapeutic 

drug monitoring of sirolimus: effect of concomitant 

immunosuppressive therapy and optimization of drug 

dosing. Am J Transplant 2004;4(8):1345-51. 

Excluded because MPA not measured in blood 

Cattaneo D, Merlini S, Zenoni S, et al. Influence of comedication with sirolimus or cyclosporine on 

mycophenolic acid pharmacokinetics in kidney 

transplantation. Am J Transplant 2005;5(12):2937-44. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Ceglarek U, Casetta B, Lembcke J, et al. Inclusion of MPA 

and in a rapid multi-drug LC-tandem mass spectrometric 

method for simultaneous determination of 

immunosuppressants. Clin Chim Acta 2006;373(1-2):168-

71. 

Excluded because not a full report of an included study 

type 

Chen H, Peng C, Yu Z, et al. Pharmacokinetics of 

mycophenolic acid and determination of 

area under the curve by abbreviated sampling strategy in 

Chinese liver transplant recipients. Clin Pharmacokinet 

2007;46(2):175-85. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Chen YH, Zheng KL, Chen LZ, et al. Clinical 

pharmacokinetics of tacrolimus after the first oral 

administration in combination with mycophenolate mofetil 

and prednisone in Chinese renal transplant recipients. 

Transplant Proc 2005;37(10):4246-50. 

Excluded because MPA not measured in blood 

Chenhsu RY, Wu YM, Min DI, et al. Effects of 

mycophenolate mofetil on hematocrit after renal 

transplantation. Ann Pharmacother 2002;36(9):1479-80. 

Excluded because not a full report of an included study 

type 

Cho EK, Han DJ, Kim SC, et al. Pharmacokinetic study of 

mycophenolic acid in Korean kidney transplant patients. J 

Clin Pharmacol 2004;44(7):743-50. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Cibrik D, Meier-Kriesche HU, Bresnahan B, et al. Renal 

function with cyclosporine C2 monitoring, enteric-coated 

mycophenolate sodium and basiliximab: a 12-month 

randomized trial in renal transplant recipients. Clin 

Transplant 2007;21(2):192-201. 

Excluded because MPA not measured in blood 

Cremers S, Schoemaker R, Scholten E, et al. 

Characterizing the role of enterohepatic recycling in the 

interactions between mycophenolate mofetil and 

calcineurin inhibitors in renal transplant patients by 

pharmacokinetic modelling. Br J Clin Pharmacol 

2005;60(3):249-56. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Cussonneau X, Bolon-Larger M, Prunet-Spano C, et al. 

Relationship between MPA free fraction and free MPAG 

concentrations in heart transplant recipients based on 

simultaneous HPLC quantification of the target compounds 

in human plasma. J Chromatogr B Analyt Technol Biomed 

Life Sci 2007;852(1-2):674-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Czock D, Rasche FM, Carius A, et al. Pharmacokinetics 

and pharmacodynamics of mycophenolic acid after entericcoated mycophenolate versus mycophenolate mofetil in 

patients with progressive IgA nephritis. J Clin Pharmacol 

2007;47(7):850-9. 

Excluded because does not report on humans with a solid 

organ transplant 

Dall'Amico R, Ghiggeri G, Carraro M, et al. Prediction 

and treatment of recurrent focal segmental 

glomerulosclerosis after renal transplantation in children. 

Am J Kidney Dis 1999;34(6):1048-55. 

Excluded because MPA not measured in blood 
D-5

David-Neto E, Pereira Araujo LM, Sumita NM, et al. 

Mycophenolic acid pharmacokinetics in stable pediatric 

renal transplantation. Pediatr Nephrol 2003;18(3):266-72. 

Excluded because MPA levels not associated with any 

clinical outcomes 

David-Neto E, Pereira LM, Kakehashi E, et al. The need of 

mycophenolic acid monitoring in long-term renal 

transplants. Clin Transplant 2005;19(1):19-25. 

Excluded because MPA levels not associated with any 

clinical outcomes 

De Geest S, Denhaerynck K, Schafer-Keller P, et al. 

Supporting medication adherence in renal transplantation - 

The SMART study. Swiss Medical Weekly 

2007;137(SUPPL 155):125S-7S. 

Excluded because MPA not measured in blood 

Devyatko E, Ploner M, Zuckermann A, et al. Value of 

mycophenolic acid trough level monitoring after lung 

transplantation. Transplant Proc 2002;34(5):1881-3. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Devyatko E, Zuckermann A, Bohdjalian A, et al. 

Activation of the purine salvage pathway in mononuclear 

cells of cardiac recipients treated with mycophenolate 

mofetil. Transplantation 2006;82(1):113-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Dharancy S, Hulin A, Declerck N, et al. Mycophenolic 

acid (MPA) AUC(0-12H) in stable liver transplant patients 

treated with a monotherapy of mycophenolate mofetil 

(MMF) for calcineurin inhibitors (CNI) induced 

nephrotoxicity. Hepatology 2006;44(4, Suppl. 1):406A7A. 

Excluded because not a full report of an included study 

type 

Di Benedetto F, Di Sandro S, De Ruvo N, et al. Sirolimus 

Monotherapy in Liver Transplantation. Transplantat Proc 

2007;39(6):1930-2. 

Excluded because MPA not measured in blood 

Diekmann F, Campistol JM, Saval N, et al. Sequential 

quadruple immunosuppression including sirolimus in 

extended criteria and nonheartbeating donor kidney 

transplantation. Transplantation 2007;84(3):429-32. 

Excluded because not a full report of an included study 

type 

Djebli N, Picard N, Rerolle JP, et al. Influence of the 

UGT2B7 promoter region and exon 2 polymorphisms and 

comedications on Acyl-MPAG production in vitro and in 

adult renal transplant patients. Pharmacogenet Genomics 

2007;17(5):321-30. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Doria C, Fraser N, Ramirez CB, et al. Use of EC-MPS 

(MYFORTIC (R), enteric coated mycophenolate sodium) 

as part of immunosuppression regimen in liver transplant 

patients suffering from intestinal intolerance and/or poor 

quality of life related to the use mycophenolate mofetil 

(MMF). Hepatology 2006;44(4, Suppl. 1):411A-2A. 

Excluded because not a full report of an included study 

type 

Dosch AO, Ehlermann P, Koch A, et al. A comparison of 

measured trough levels and abbreviated AUC estimation by 

limited sampling strategies for monitoring mycophenolic 

acid exposure in stable heart transplant patients receiving 

cyclosporin A-containing and cyclosporin A-free 

immunosuppressive regimens. Clin Ther 2006;28(6):893-

905. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Drognitz O, Donauer J, Kamgang J, et al. Living-donor 

kidney transplantation: The Freiburg experience. 

Langenbecks Arch Surg 2007;392(1):23-33. 

Excluded because MPA not measured in blood 

Ducloux D, Motte G, Billerey C, et al. Cyclosporin 

withdrawal with concomitant conversion from azathioprine 

to mycophenolate mofetil in renal transplant recipients with 

chronic allograft nephropathy: a 2-year follow-up. Transpl 

Int 2002;15(8):387-92. 

Excluded because MPA not measured in blood 

El Haggan W, Ficheux M, Debruyne D, et al. 

Pharmacokinetics of mycophenolic acid in kidney 

transplant patients receiving sirolimus versus cyclosporine. 

Transplant Proc 2005;37(2):864-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Engelbertink R, Smak GP, Hesse C, et al. High 

mycophenolic acid area under-the-curve values in renal 

transplant recipients on long-term mycophenolate mofetil 

treatment. Transplant Proc 2002;34(7):2983-4. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Ensom MH, Partovi N, Decarie D, et al. Pharmacokinetics 

and protein binding of mycophenolic acid in stable lung 

transplant recipients. Ther Drug Monit 2002;24(2):310-4. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Ensom MH, Partovi N, Decarie D, et al. Mycophenolate 

pharmacokinetics in early period following lung or heart 

transplantation. Ann Pharmacother 2003;37(12):1761-7. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Esmatjes E, Flores L, Vidal M, et al. Hypoglycaemia after 

pancreas transplantation: Usefulness of a continuous 

glucose monitoring system. Clin Transplant 

2003;17(6):534-8. 

Excluded because MPA not measured in blood 
D-6

Ettenger R, Bartosh S, Choi L, et al. Pharmacokinetics of 

enteric-coated mycophenolate sodium in stable pediatric 

renal transplant recipients. Pediatr Transplant 

2005;9(6):780-7. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Fatela-Cantillo D, Hinojosa-Perez R, Peralvo-Rodriguez 

MI, et al. Pharmacokinetic Evaluation of Mycophenolic 

Acid Profiles During the Period Immediately Following an 

Orthotopic Liver Transplant. Transplant Proc 

2006;38(8):2482-5. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Fernandez A, Martins J, Villlafruela JJ, et al. Variability of 

mycophenolate mofetil trough levels in stable kidney 

transplant patients. Transplant Proc 2007;39(7):2185-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Fernandez A, Marcen R, Pascual J, et al. Mycophenolate 

mofetil levels in stable kidney transplant recipients. 

Transplant Proc 2007;39(7):2182-4. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Ferraris JR, Ghezzi L, Waisman G, et al. Potential 

cardiovascular risk factors in paediatric renal transplant 

recipients. Pediatr Nephrol 2006;21(1):119-25. 

Excluded because MPA not measured in blood 

Figueras J, Prieto M, Bernardos A, et al. Daclizumab 

induction and maintenance steroid-free immunosuppression 

with mycophenolate mofetil and tacrolimus to prevent 

acute rejection of hepatic allografts. Transpl Int 

2006;19(8):641-8. 

Excluded because MPA not measured in blood 

Filler G, Zimmering M, Mai I. Pharmacokinetics of 

mycophenolate mofetil are influenced by concomitant 

immunosuppression. Pediatr Nephrol 2000;14(2):100-4. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Filler G, Lepage N, Delisle B, et al. Effect of cyclosporine 

on mycophenolic acid area under the concentration-time 

curve in pediatric kidney transplant recipients. Ther Drug 

Monit 2001;23(5):514-9. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Filler G, Feber J. The transplanted child: New 

immunosuppressive agents and the need for 

pharmacokinetic monitoring. Paediatrics and Child Health 

2002;7(8):525-32. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Filler G, Feber J, Lepage N, et al. Universal approach to 

pharmacokinetic monitoring of 

immunosuppressive agents in children. Pediatr Transplant 

2002;6(5):411-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Filler G. Abbreviated mycophenolic acid AUC from C0, 

C1, C2, and C4 is preferable in children after renal 

transplantation on mycophenolate mofetil and tacrolimus 

therapy. Transpl Int 2004;17(3):120-5. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Filler G, Foster J, Berard R, et al. Age-dependency of 

mycophenolate mofetil dosing in combination with 

tacrolimus after pediatric renal transplantation. Transplant 

Proc 2004;36(5):1327-31. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Filler G, De Barros VR, Jagger JE, et al. Cyclosporin twice 

or three times daily dosing in pediatric transplant patients - 

It is not the same! Pediatr Transplant 2006;10(8):953-6. 

Excluded because MPA not measured in blood 

Filler G. Optimization of Immunosuppressive Drug 

Monitoring in Children. Transplant Proc 2007;39(4):1241-

3. 

Excluded because not a full report of an included study 

type 

Firpi RJ, Nelson DR, Davis GL. Lack of antiviral effect of 

a short course of mycophenolate mofetil in patients with 

chronic hepatitis C virus infection. Liver Transpl 

2003;9(1):57-61. 

Excluded because MPA not measured in blood 

Flechner SM, Goldfarb D, Modlin C, et al. Kidney 

transplantation without calcineurin inhibitor drugs: a 

prospective, randomized trial of sirolimus versus 

cyclosporine. Transplantation 2002;74(8):1070-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Flechner SM, Goldfarb D, Solez K, et al. Kidney 

transplantation with sirolimus and mycophenolate mofetilbased immunosuppression: 5-year results of a randomized 

prospective trial compared to calcineurin inhibitor drugs. 

Transplantation 2007;83(7):883-92. 

Excluded because MPA not measured in blood 

Fleming DH, Mathew BS, John GT, et al. A six-hour 

extrapolated sampling strategy for monitoring 

mycophenolic acid in renal transplant patients in the Indian 

subcontinent. J Postgrad Med 2006;52(4):248-52. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Folkmane I, Bernarde K, Bicans J, et al. Beneficial effects 

of low-toxicity regimens with MMF in renal recipients with 

late allograft dysfunction. Transplant Proc 2003;35(2):789-

90. 

Excluded because MPA not measured in blood 
D-7

Funch DP, Ko HH, Travasso J, et al. Posttransplant 

lymphoproliferative disorder among renal transplant 

patients in relation to the use of mycophenolate mofetil. 

Transplantation 2005;80(9):1174-80. 

Excluded because MPA not measured in blood 

Galiwango P, Delgado D, Ross H. Dose reduction of MMF 

due to gastrointestinal intolerance is associated with 

increased rejection in heart transplant recipients. J Heart 

Lung Transplant 2007;26(2, Suppl. S):S70-S71 

Excluded because not a full report of an included study 

type 

Gallon LG, Winoto J, Chhabra D, et al. Long-term renal 

transplant function in recipient of simultaneous kidney and 

pancreas transplant maintained with two prednisone-free 

maintenance immunosuppressive combinations: 

acrolimus/mycophenolate mofetil versus 

tacrolimus/sirolimus. Transplantation 2007;83(10):1324-9. 

Excluded because MPA not measured in blood 

Garcia CD, Bittencourt VB, Tumelero A, et al. 

Plasmapheresis for recurrent posttransplant focal segmental 

glomerulosclerosis. Transplant Proc 2006;38(6):1904-5. 

Excluded because MPA not measured in blood 

Garcia R, Machado PG, Felipe CR, et al. Exploratory 

calcineurin inhibitor-free regimens in living-related kidney 

transplant recipients. Braz J Med Biol Res 2007;40(4):457-

65. 

Excluded because MPA not measured in blood 

Garlicki M, Kolcz J, Rudzinski P, et al. Myocardial 

protection for transplantation. Transplant Proc 

1999;31(5):2079-83. 

Excluded because MPA not measured in blood 

Gelone DK, Park JM, Lake KD. Lack of an effect of oral 

iron administration on mycophenolic acid 

pharmacokinetics in stable renal transplant recipients. 

Pharmacotherapy 2007;27(9):1272-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Genctoy G, Kahraman S, Arici M, et al. The role of 

proinflammatory cytokine gene polymorphisms for 

development of insulin resistance after renal 

transplantation. Transplant Proc 2006;38(2):521-8. 

Excluded because MPA not measured in blood 

Ghafari A, Makhdoomi K, Ahmadpour P, et al. Low-Dose 

Versus High-Dose Cyclosporine 

Induction Protocols in Renal Transplantation. 

Transplantation Proceedings 39(4)()(pp 

1219-1222), 2007 Date of Publication: May 2007 

2007;(4):1219-22. 

Excluded because MPA not measured in blood 

Ghio L, Ferraresso M, Vigano SM, et al. Mycophenolate 

mofetil pharmacokinetic monitoring in pediatric kidney 

transplant recipients. Transplant Proc 2005;37(2):856-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Ghobrial RM, Holt CD, Sievers TM, et al. Mycophenolate 

mofetil in liver transplantation for hepatitis C: effect on 

recurrence and pharmacokinetics. Am J Transplant 

2004;4(Suppl 8):598. 

Excluded because not a full report of an included study 

type 

Gimenez F, Foeillet E, Bourdon O, et al. Evaluation of 

pharmacokinetic interactions after oral administration of 

mycophenolate mofetil and valaciclovir or aciclovir to 

healthy subjects. Clin Pharmacokinet 2004;43(10):685-92. 

Excluded because does not report on humans with a solid 

organ transplant 

Glander P, Hambach P, Braun KP, et al. Effect of 

mycophenolate mofetil on IMP dehydrogenase after the 

first dose and after long-term treatment in renal transplant 

recipients. Int J Clin Pharmacol Ther 2003;41(10):470-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Glander P, Hambach P, Braun KP, et al. Pre-transplant 

inosine monophosphate dehydrogenase activity is 

associated with clinical outcome after renal transplantation. 

Am J Transplant 2004;4(12):2045-51. 

Excluded because MPA not measured in blood 

Goel M, Flechner SM, Zhou L, et al. The influence of 

various maintenance immunosuppressive drugs on 

lymphocele formation and treatment after kidney 

transplantation. J Urol 2004;171(5):1788-92. 

Excluded because MPA not measured in blood 

Goldsmith D, Carrey EA, Edbury S, et al. Mycophenolate 

mofetil, an inhibitor of inosine monophosphate 

dehydrogenase, causes a paradoxical elevation of GTP in 

erythrocytes of renal transplant patients. Clin Sci 

2004;107(1):63-8. 

Excluded because MPA not measured in blood 

Gomard-Mennesson E, Ruivard M, Koenig M, et al. 

Treatment of isolated severe immune hemolytic anaemia 

associated with systemic lupus erythematosus: 26 Cases. 

Lupus 2006;15(4):223-31. 

Excluded because does not report on humans with a solid 

organ transplant 

Gonwa T, Mendez R, Yang HC, et al. Randomized trial of 

tacrolimus in combination with sirolimus or mycophenolate 

mofetil in kidney transplantation: results at 6 months. 

Transplantation 2003;75(8):1213-20. 

Excluded because MPA not measured in blood 

Gonzalez-Roncero FM, Govantes MA, Chaves VC, et al. 

Influence of Renal Insufficiency on Pharmacokinetics of 

ACYL-Glucuronide Metabolite of Mycophenolic Acid in 

Renal Transplant Patients. Transplant Proc 2007;39(7): 

2176-8. 
D-8

Excluded because MPA levels not associated with any 

clinical outcomes 

Gonzalez MM, Seron D, Garcia DM, et al. Mycophenolate 

mofetil reduces deterioration of renal function in patients 

with chronic allograft nephropathy. A follow-up study by 

the Spanish Cooperative Study Group of Chronic Allograft 

Nephropathy. Transplantation 2004;77(2):215-20. 

Excluded because MPA not measured in blood 

Goossens VJ, Christiaans MH, Blok MJ, et al. Onset and 

duration of cytomegalovirus immediate early 1 mRNA 

expression in the blood of renal transplant recipients. J 

Med Virol 2004;72(1):94-101. 

Excluded because MPA not measured in blood 

Graff J, Klinkhardt U, Harder S, et al. Immunosuppressive 

therapy regimen and platelet activation in renal transplant 

patients. Clin Pharmacol Ther 2002;72(4):411-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Gregoor PJ, De Sevaux RG, Hene RJ, et al. Effect of 

cyclosporine on mycophenolic acid trough levels in kidney 

transplant recipients. Transplantation 1999;68(10):1603-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Griesmacher A, Weigel G, Seebacher G, et al. Inhibition of 

inosine monophosphate dehydrogenase activity by the 

plasma of heart transplant recipients receiving 

mycophenolate mofetil. Adv Exp Med Biol 1998;431:537-

41. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Griesmacher A, Weigel G, Seebacher G, et al. Guanosine5'-triphosphate increases in red blood cells of heart 

transplant recipients treated with mycophenolate mofetil. 

Adv Exp Med Biol 2000;486:139-43. 

Excluded because MPA not measured in blood 

Guleria S, Kamboj M, Singh P, et al. Tacrolimus (Pan 

Graf) as de Novo Therapy in Renal Transplant Recipients 

in India. Transplant Proc 2006;38(7):2029-31. 

Excluded because MPA not measured in blood 

Hafiz MM, Faradji RN, Froud T, et al. 

Immunosuppression and procedure-related complications in 

26 patients with type 1 diabetes mellitus receiving 

allogeneic islet cell 

transplantation. Transplantation 2005;80(12):1718-28. 

Excluded because does not report on humans with a solid 

organ transplant 

Halloran P, Mathew T, Tomlanovich S. Erratum: 

Mycophenolate mofetil in renal allograft recipients: A 

polled efficacy analysis of three randomized, double-blind, 

clinical studies in prevention of rejection (Transplantation 

(January 15, 1997) 63:39 (43-44)). Transplantation 

1997;63(4):618 

Excluded because not a full report of an included study 

type 

Hanto DW, Fecteau AH, Alonso MH, et al. ABOincompatible liver transplantation with no immunological 

graft losses using total plasma exchange, splenectomy, and 

quadruple immunosuppression: evidence for 

accommodation. Liver Transpl 2003;9(1):22-30. 

Excluded because MPA not measured in blood 

Hariharan S. Case 3: New clinical trials in renal 

transplantation. Transplantation (Hagerstown) 

2003;75(7):1084-7. 

Excluded because not a full report of an included study 

type 

Havrdova T, Saudek F, Boucek P, et al. Metabolic effect 

of sirolimus versus mycophenolate mofetil on pancreatic 

graft function - a prospective randomised study. 

Diabetologia 2006;49(Suppl. 1):150-1. 

Excluded because not a full report of an included study 

type 

Hazzan M, Buob D, Labalette M, et al. Assessment of the 

risk of chronic allograft dysfunction after renal 

transplantation in a randomized cyclosporine withdrawal 

trial. Transplantation 2006;82(5):657-62. 

Excluded because MPA not measured in blood 

Hocker B, Weber LT, Bunchman T, et al. Mycophenolate 

mofetil suspension in pediatric renal transplantation: threeyear data from the tricontinental trial. Pediatr Transplant 

2005;9(4):504-11. 

Excluded because MPA not measured in blood 

Hohage H, Zeh M, Heck M, et al. Differential effects of 

cyclosporine and tacrolimus on mycophenolate 

pharmacokinetics in patients with impaired kidney 

function. Transplant Proc 2005;37(4):1748-50. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Hricik DE, Anton HA, Knauss TC, et al. Outcomes of 

African American kidney transplant recipients treated with 

sirolimus, tacrolimus, and corticosteroids. Transplantation 

2002;74(2):189-93. 

Excluded because MPA not measured in blood 

Hubner GI, Eismann R, Sziegoleit W. Drug interaction 

between mycophenolate mofetil and tacrolimus detectable 

within therapeutic mycophenolic acid monitoring in renal 

transplant patients. Ther Drug Monit 1999;21(5):536-9. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Humar A, Crotteau S, Gruessner A, et al. Steroid 

minimization in liver transplant recipients: Impact on 

hepatitis C recurrence and post-transplant diabetes. Clin 

Transplant 2007;21(4):526-31. 

Excluded because MPA not measured in blood 
D-9

Hummel M, Yonan N, Ross H, et al. Pharmacokinetics and 

variability of mycophenolic acid from enteric-coated 

mycophenolate sodium compared with mycophenolate 

mofetil in de novo heart transplant recipients. Clin 

Transplant 2007;21(1):18-23. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Hutchinson P, Chadban SJ, Atkins RC, et al. Laboratory 

assessment of immune function in renal transplant patients. 

Nephrol Dial Transplant 2003;18(5):983-9. 

Excluded because MPA not measured in blood 

Hymes LC, Greenbaum L, Amaral SG, et al. Surveillance 

renal transplant biopsies and subclinical rejection at three 

months post-transplant in pediatric recipients. Pediatr 

Transplant 2007;11(5):536-9. 

Excluded because MPA not measured in blood 

Inoue K, Miura M, Satoh S, et al. Influence of UGT1A7 

and UGT1A9 intronic I399 genetic polymorphisms on 

mycophenolic acid pharmacokinetics in Japanese renal 

transplant recipients. Ther Drug Monit 2007;29(3):299-

304. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Jacobson PA, Green KG, Hering BJ. Mycophenolate 

mofetil in islet cell transplant: Variable pharmacokinetics 

but good correlation between total and unbound 

concentrations. J Clin Pharmacol 2005;45(8):901-9. 

Excluded because does not report on humans with a solid 

organ transplant 

Jacqz-Aigrain E, Khan SE, Baudouin V, et al. 

Pharmacokinetics and tolerance of mycophenolate mofetil 

in renal transplant children. Pediatr Nephrol 

2000;14(2):95-9. 

Excluded because MPA levels not associated with any 

clinical outcomes Jain A, Venkataramanan R, Hamad IS, et 

al. Pharmacokinetics of mycophenolic acid after 

mycophenolate mofetil administration in liver transplant 

patients treated with tacrolimus. J Clin Pharmacol 

2001;41(3):268-76. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Jain A, Venkataramanan R, Kwong T, et al. 

Pharmacokinetics of mycophenolic acid in Liver transplant 

patients after intravenous and oral administration of 

mycophenolate mofetil. Liver Transpl 2007;13(6):791-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Jain AB, Hamad I, Zuckerman S, et al. Effect of t-tube 

clamping on the pharmacokinetics 

of mycophenolic acid in liver transplant patients on oral 

therapy of mycophenolate 

mofetil. Liver Transplantation and Surgery 1999;5(2):101-

6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Ji S-M, Liu Z-H, Chen J-S, et al. Rescue Therapy by 

Immunoadsorption in Combination With Tacrolimus and 

Mycophenolate Mofetil for C4d-Positive Acute Humoral 

Renal Allograft Rejection. Transplant Proc 

2006;38(10):3459-63. 

Excluded because MPA not measured in blood 

Ji S-M, Li L-S, Cheng Z, et al. A Single-dose Daclizumab 

Induction Protocol in Renal Allograft Recipients: A 

Chinese Single Center Experience. Transplant Proc 2007; 

39(5):1396-1401. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Jiao Z, Zhong J-Y, Zhang M, et al. Total and free 

mycophenolic acid and its 7-O-glucuronide metabolite in 

Chinese adult renal transplant patients: Pharmacokinetics 

and application of limited sampling strategies. Eur J Clin 

Pharmacol 2007;63(1):27-37. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Jiao Z, Shen B, Zhang M, et al. Population 

pharmacokinetics of mycophenolic acid in Chinese adult 

renal transplant recipients during the first month after 

transplantation. Acta Pharmacologica Sinica 

2006;27(Suppl. 1): 

Excluded because not a full report of an included study 

type 

Jirasiritham S, Sumethkul V, Mavichak V, et al. The 

pharmacokinetics of mycophenolate mofetil in Thai kidney 

transplant recipients. Transplant Proc 2004;36(7):2076-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Johnson L, Oetting W, Basu S, et al. Pharmacogenetics of 

mycophenolate in kidney transplantation. Clin Pharmacol 

Ther 2007;81(Suppl. 1):S32-S33 

Excluded because not a full report of an included study 

type 

Jorgensen KA, Povlsen JV, Madsen S, et al. Two-hour 

blood tacrolimus levels are not superior to trough levels as 

estimates of the area under the curve in tacrolimus-treated 

renal transplant patients. Transplant Proc 2002;34(5):1721-

2. 

Excluded because MPA not measured in blood 

Julasareekul W, Eiam-Ong S, Bejraputra O, et al. 

Pharmacokinetics of mycophenolic acid in kidney 

transplant recipients treated with a low dose (1 gram/day) 

of mycophenolate mofetil. J Med Assoc Thai 

2003;86(8):766-71. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Jungraithmayr TC, Wiesmayr S, Staskewitz A, et al. Fiveyear outcome in pediatric patients with mycophenolate 

mofetil-based renal transplantation. Transplantation 

2007;83(7):900-5. 
D-10

Excluded because MPA not measured in blood 

Kagaya H, Inoue K, Miura M, et al. Quantification and 24-

hour monitoring of mycophenolic acid by highperformance liquid chromatography in Japanese renal 

transplant recipients. Yakugaku Zasshi 

2006;126(12):1357-62. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Kagaya H, Inoue K, Miura M, et al. Influence of UGT1A8 

and UGT2B7 genetic polymorphisms on mycophenolic 

acid pharmacokinetics in Japanese renal transplant 

recipients. Eur J Clin Pharmacol 2007;63(3):279-88. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Kagaya H, Inoue K, Miura M, et al. Quantification and 24-

hour monitoring of mycophenolic acid by highperformance liquid chromatography in Japanese renal 

transplant recipients. Yakugaku Zasshi 

2006;126(12):1357-62. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Kahan BD. High variability of drug exposure: a 

biopharmaceutic risk factor for chronic rejection. 

Transplant Proc 1998;30(5):1639-41. 

Excluded because not a full report of an included study 

type 

Kamar N, Oufroukhi L, Sallusto F, et al. Impact of 

mycophenolic acid dose modifications on renal function 

after kidney transplantation. Exp Clin Transplant 

2006;4(2):510-7. 

Excluded because MPA not measured in blood 

Kaplan B, Meier-Kriesche HU, Minnick P, et al. 

Randomized calcineurin inhibitor cross 

over study to measure the pharmacokinetics of coadministered enteric-coated mycophenolate sodium. Clin 

Transplant 2005;19(4):551-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Kato R, Ooi K, Ikura-Mori M, et al. Impairment of 

mycophenolate mofetil absorption by 

calcium polycarbophil. J Clin Pharmacol 

2002;42(11):1275-80. 

Excluded because does not report on humans with a solid 

organ transplant 

Kausman JY, Powell HR, Jones CL. Anemia in pediatric 

renal transplant recipients. Pediatr Nephrol 

2004;19(5):526-30. 

Excluded because MPA not measured in blood 

Keogh A. Long-term benefits of mycophenolate mofetil 

after heart transplantation. 

Transplantation (Hagerstown) 2005;79(3, Suppl. S):S45-

S46 

Excluded because MPA not measured in blood 

Keven K, Sahin M, Kutlay S, et al. Immunoglobulin 

deficiency in kidney allograft recipients: comparative 

effects of mycophenolate mofetil and azathioprine. 

Transplant Infectious Disease 2003;5(4):181-6. 

Excluded because MPA not measured in blood 

Khosroshahi HT, Asghari A, Estakhr R, et al. Effects of 

Azathioprine and Mycophenolate MofetilImmunosuppressive Regimens on the Erythropoietic 

System of Renal Transplant Recipients. Transplant Proc 

2006;38(7):2077-9. 

Excluded because MPA not measured in blood 

Khosroshahi HT, Nahali A, Gojazadeh M, et al. 

Comparison of Transplanted Kidney Function in Patients 

on Two Different Doses of Mycophenolate Mofetil. 

Transplant Proc 2006;38(7):2035-7. 

Excluded because MPA not measured in blood 

Kiberd BA, Puthenparumpil JJ, Fraser A, et al. Impact of 

mycophenolate mofetil loading on drug exposure in the 

early posttransplant period. Transplant Proc 

2005;37(5):2320-3. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Kim MJ, Mayr M, Pechula M, et al. Marked erythrocyte 

microcytosis under primary immunosuppression with 

sirolimus. Transpl Int 2006;19(1):12-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Kirsch BM, Haidinger M, Zeyda M, et al. Alemtuzumab 

(Campath-1H) induction therapy and dendritic cells: Impact 

on peripheral dendritic cell repertoire in renal allograft 

recipients. Transpl Immunol 2006;16(3-4):254-7. 

Excluded because MPA not measured in blood 

Knight RJ, Kerman RH, McKissick E, et al. A pilot study 

of immunosuppression minimization after pancreas-kidney 

transplantation utilizing thymoglobulin induction and 

sirolimus maintenance therapy. Transplant Proc 

2005;37(8):3538-41. 

Excluded because MPA not measured in blood 

Kobashigawa JA, Miller LW, Russell SD, et al. 

Tacrolimus with mycophenolate mofetil (MMF) or 

sirolimus vs. cyclosporine with MMF in cardiac transplant 

patients: 1-year report. Am J Transplant 2006;6(6):1377-

86. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Kobashigawa JA, Renlund DG, Gerosa G, et al. Similar 

efficacy and safety of enteric-coated mycophenolate 

sodium (EC-MPS, myfortic) compared with mycophenolate 

mofetil (MMF) in de novo heart transplant recipients: 

Results of a 12-month, single-blind, randomized, parallelgroup, multicenter study. J Heart Lung Transplant 

2006;25(8):935-41. 

Excluded because MPA not measured in blood 
D-11

Kocik M, Malek I, Glagolicova A, et al. The effect of 

cyclosporin A on the level of big endothelin in patients one 

year after orthotopic heart transplantation. Transpl Int 

2004;17(2):65-70. 

Excluded because MPA not measured in blood 

Kreis H. Worse renal transplant outcomes with sirolimusmycophenolate than with calcineurin inhibitor regimens. 

Nature Clinical Practice Nephrology 2007;3(8):424-5. 

Excluded because not a full report of an included study 

type 

Kuriata-Kordek M, Boratynska M, Falkiewicz K, et al. 

The influence of calcineurin inhibitors on mycophenolic 

acid pharmacokinetics. Transplant Proc 2003;35(6):2369-

71. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Kuypers DR, Claes K, Evenepoel P, et al. Time-related 

clinical determinants of long-term tacrolimus 

pharmacokinetics in combination therapy with 

mycophenolic acid and corticosteroids: a prospective study 

in one hundred de novo renal transplant recipients. 

Clin Pharmacokinet 2004;43(11):741-62. 

Excluded because MPA not measured in blood 

Lage E, Ballesteros S, Mogollon MV, et al. Is It Possible 

to Reduce the Number of Endomyocardial Biopsies With 

New Immunosuppressive Drugs? Transplant Proc 

2006;38(8):2544-6. 

Excluded because MPA not measured in blood 

Land W, Schneeberger H, Weiss M, et al. Mycophenolate 

mofetil monotherapy: an optimal, safe, and efficacious 

immunosuppressive maintenance regimen in kidney 

transplant patients. Transplant Proc 

2001;33(4:Suppl):Suppl-35S 

Excluded because MPA not measured in blood 

Langman LJ, LeGatt DF, Halloran PF, et al. 

Pharmacodynamic assessment of mycophenolic acidinduced immunosuppression in renal transplant recipients. 

Transplantation 1996;62(5):666-72. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Langrehr JM, Klupp J, Glanemann M, et al. Long-term 

results of mycophenolate mofetil as part of 

immunosuppressive induction therapy after liver 

transplantation. Clin Transplant 2006;20(3):272-83. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Le Guellec C, Buchler M, Giraudeau B, et al. 

Simultaneous estimation of cyclosporin and 

mycophenolic acid areas under the curve in stable renal 

transplant patients using a limited sampling strategy. Eur J 

Clin Pharmacol 2002;57(11):805-11. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Le Guellec C, Bourgoin H, Buchler M, et al. Population 

pharmacokinetics and Bayesian estimation of 

mycophenolic acid concentrations in stable renal transplant 

patients. Clin Pharmacokinet 2004;43(4):253-66. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Leogrande D, Teutonico A, Ranieri E, et al. Monitoring 

biological action of rapamycin in renal transplantation. Am 

J Kidney Dis 2007;50(2):314-25. 

Excluded because MPA not measured in blood 

Lessan-Pezeshki M. Pregnancy after renal transplantation: 

Points to consider. Nephrol Dial Transplant 2002;17(5): 

703-7. 

Excluded because not a full report of an included study 

type 

Lessan-Pezeshki M, Amirzargar A, Fathi A, et al. Value of 

pretransplantation cytokine profiles for predicting acute 

rejection in renal transplant recipients. Transplant Proc 

2005;37(7):2982-4. 

Excluded because MPA not measured in blood 

Li H, Tanaka K, Chhabra A, et al. Vascular remodeling 1 

year after cardiac transplantation. J Heart Lung Transplant 

2007;26(1):56-62. 

Excluded because MPA not measured in blood 

Liang MZ, Lu YP, Nan F, et al. Pharmacokinetics of 

Mycophenolic Acid and Its Glucuronide After a Single and 

Multiple Oral Dose of Mycophenolate Mofetil in Chinese 

Renal Transplantation Recipients. Transplant Proc 

2006;38(7):2044-7. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Lira MG, Provezza L, Malerba G, et al. Glutathione Stransferase and CYP1A1 gene polymorphisms and nonmelanoma skin cancer risk in Italian transplanted patients. 

Exp Dermatol 2006;15(12):958-65. 

Excluded because MPA not measured in blood 

Loinaz C, Kato T, Nishida S, et al. Bacterial infections 

after intestine and multivisceral transplantation. The 

experience of the University of Miami (1994-2001). 

Hepatogastroenterology 2006;53(68):234-42. 

Excluded because MPA not measured in blood 

Lorenz M, Wolzt M, Weigel G, et al. Ferrous sulfate does 

not affect mycophenolic acid pharmacokinetics in kidney 

transplant patients. Am J Kidney Dis 2004;43(6):1098-

103. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Mai I, Stormer E, Bauer S, et al. Impact of St John's wort 

treatment on the pharmacokinetics of tacrolimus and 

mycophenolic acid in renal transplant patients. Nephrol 

Dial Transplant 2003;18(4):819-22. 

Excluded because MPA levels not associated with any 

clinical outcomes 
D-12

Mardigyan V, Giannetti N, Cecere R, et al. Best single 

time points to predict the area-under-the-curve in long-term 

heart transplant patients taking mycophenolate mofetil 

in combination with cyclosporine or tacrolimus. J Heart 

Lung Transplant 2005;24(10):1614-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Mardigyan V, Tchervenkov J, Metrakos P, et al. Best 

single time points as surrogates to the tacrolimus and 

mycophenolic acid area under the curve in adult liver 

transplant patients beyond 12 months of transplantation. 

Clin Ther 2005;27(4):463-9. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Margolis DM, Kewn S, Coull JJ, et al. The addition of 

mycophenolate mofetil to antiretroviral therapy including 

abacavir is associated with depletion of intracellular 

deoxyguanosine triphosphate and a decrease in plasma 

HIV-1 RNA. Journal of Acquired Immune Deficiency 

Syndromes: JAIDS 2002;31(1):45-9. 

Excluded because does not report on humans with a solid 

organ transplant 

Martins L, Pedroso S, Henriques AC, et al. Simultaneous 

pancreas-kidney transplantation: five-year results from a 

single center. Transplant Proc 2006;38(6):1929-32. 

Excluded because MPA not measured in blood 

Masri MA, Rizk S, Attia MLE, et al. Bioavailability of a 

New Generic Formulation of Mycophenolate Mofetil MMF 

500 Versus CellCept in Healthy Adult Volunteers. 

Transplantation Proceedings 39(4)()(pp 1233-1236), 2007 

Date of Publication: May 2007 

2007;(4):1233-6. 

Excluded because does not report on humans with a solid 

organ transplant 

Matas AJ, Kandaswamy R, Humar A, et al. Long-term 

immunosuppression, without maintenance prednisone, after 

kidney transplantation. Ann Surg 2004;240(3):510-7. 

Excluded because MPA not measured in blood 

Mathew JM, Carreno M, Fuller L, et al. In vitro 

immunogenicity of cadaver donor bone 

marrow cells used for the induction of allograft acceptance 

in clinical transplantation. 

Transplantation 1999;68(8):1172-80. 

Excluded because not a full report of an included study 

type 

Matthew TH. Erratum: A blinded, long-term, randomized 

multicenter study of mycophenolate mofetil in cadaveric 

renal transplantation: Results at three years Transplantation 

(June 15, 1998) 65:11 (1450)). Transplantation 

1998;66(6):817 

Excluded because not a full report of an included study 

type 

McDiarmid SV. Mycophenolate mofetil in liver 

transplantation. Clin Transplant 1996;10(1:Pt 2):t-5 

Excluded because MPA levels not associated with any 

clinical outcomes 

Meier-Kriesche HU, Steffen BJ, Hochberg AM, et al. 

Mycophenolate mofetil versus 

azathioprine therapy is associated with a significant 

protection against long-term renal allograft function 

deterioration. Transplantation 2003;75(8):1341-6. 

Excluded because MPA not measured in blood 

Meiser B, Van Cleemput J, Perez Villa F, et al. Trough 

level adapted mmf in combination with either tacrolimus or 

cyclosporine - The Pan-Eu-HTx trial. J Heart Lung 

Transplant 2007;26(2, Suppl. S) 

Excluded because not a full report of an included study 

type 

Meiser BM, Groetzner J, Kaczmarek I, et al. Tacrolimus or 

cyclosporine: which is the better partner for mycophenolate 

mofetil in heart transplant recipients? Transplantation 

2004;78(4):591-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Mendizabal S, Zamora I, Berbel O, et al. Mycophenolate 

mofetil in steroid/cyclosporine-dependent/resistant 

nephrotic syndrome. Pediatr Nephrol 2005;20(7):914-9. 

Excluded because does not report on humans with a solid 

organ transplant 

Miladipour AH, Ghods AJ, Nejadgashti H. Effect of 

mycophenolate mofetil on the prevention of acute renal 

allograft rejection. Transplant Proc 2002;34(6):2089-90. 

Excluded because MPA not measured in blood 

Millan O, Oppenheimer F, Brunet M, et al. Assessment of 

mycophenolic acid-induced immunosuppression: a new 

approach. Clin Chem 2000;46(9):1376-83. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Millan O, Brunet M, Campistol JM, et al. 

Pharmacodynamic approach to immunosuppressive 

therapies using calcineurin inhibitors and mycophenolate 

mofetil. Clin Chem 2003;49(11):1891-9. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Minz M, Sharma A, Heer M. Comparison of EntericCoated Mycophenolate Sodium With Mycophenolate 

Mofetil in Living Renal Allograft Transplantation. 

Transplant Proc 2006;38(7):2041-3. 

Excluded because MPA not measured in blood 

Misiakos EP, Weppler D, Neto AB, et al. The current 

status of small bowel transplantation: The experience at the 

University of Miami. Archives of Gastroenterohepatology 

1998;17(2):37-44. 

Excluded because MPA not measured in blood 

Montanaro D, Gropuzzo M, Tulissi P, et al. Effects of 

mycophenolate mofetil and azathioprine on the 
D-13

erythropoietin production in renal transplant recipients. 

Transplant Proc 2001;33(7-8):3253-5. 

Excluded because MPA not measured in blood 

Montejo M, iz ML, Zarraga S, et al. Case reports. Infection 

due to Scedosporium apiospermum in renal transplant 

recipients: A report of two cases and literature review of 

central nervous system and cutaneous infections by 

Pseudallescheria boydii/Sc. apiospermum. Mycoses 

2002;45(9-10):418-27. 

Excluded because not a full report of an included study 

type 

Moreno JM, Rubio E, Gomez A, et al. Effectiveness and 

safety of mycophenolate mofetil as monotherapy in liver 

transplantation. Transplant Proc 2003;35(5):1874-6. 

Excluded because MPA not measured in blood 

Morissette P, Albert C, Busque S, et al. In vivo higher 

glucuronidation of mycophenolic acid in male than in 

female recipients of a cadaveric kidney allograft and under 

immunosuppressive therapy with mycophenolate mofetil. 

Ther Drug Monit 2001;23(5):520-5. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Morris RG, Russ GR, Cervelli MJ, et al. Comparison of 

trough, 2-hour, and limited AUC blood sampling for 

monitoring cyclosporin (Neoral) at day 7 post-renal 

transplantation and incidence of rejection in the first month. 

Ther Drug Monit 2002;24(4):479-86. 

Excluded because MPA not measured in blood 

Mourad G, Karras A, Kamar N, et al. Renal function with 

delayed or immediate cyclosporine microemulsion in 

combination with enteric-coated mycophenolate sodium 

and steroids: results of follow up to 30 months posttransplant. Clin Transplant 2007;21(3):295-300. 

Excluded because MPA not measured in blood 

Mucha K, Foroncewicz B, Paczek L, et al. 36-month 

follow-up of 75 renal allograft 

recipients treated with steroids, tacrolimus, and 

azathioprine or mycophenolate mofetil. 

Transplant Proc 2003;35(6):2176-8. 

Excluded because MPA not measured in blood 

Muller H, Solari S, Zuniga C, et al. Therapeutic drug 

monitoring of mycophenolic acid in kidney transplant 

patients: a abbreviated sampling strategy. Transplant Proc 

2007;39(3):596-9. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Muller MM, Vogl M, Griesmacher A. Mycophenolic acid 

monitoring in HTX patients: a preliminary report. Therapie 

1997;52(4):341-4. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Munoz P, Fogeda M, Bouza E, et al. Prevalence of BK 

virus replication among recipients of solid organ 

transplants. Clin Infect Dis 2005;41(12):1720-5. 

Excluded because MPA not measured in blood 

Naderer OJ, Dupuis RE, Heinzen EL, et al. The influence 

of norfloxacin and metronidazole on the disposition of 

mycophenolate mofetil. J Clin Pharmacol 2005;45(2):219-

26. 

Excluded because does not report on humans with a solid 

organ transplant 

Naesens M, Kuypers DRJ, Streit F, et al. Rifampin induces 

alterations in mycophenolic acid glucuronidation and 

elimination: Implications for drug exposure in renal 

allograft recipients. Clin Pharmacol Ther 2006;80(5):509-

21. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Naesens M, Lerut E, Damme BV, et al. Tacrolimus 

exposure and evolution of renal allograft histology in the 

first year after transplantation. Am J Transplant 

2007;7(9):2114-23. 

Excluded because MPA not measured in blood 

Naesens M, De Loor H, Vanrenterghem Y, et al. The 

impact of renal allograft function on exposure and 

elimination of mycophenolic acid (MPA) and its metabolite 

MPA 7-O-glucuronide. Transplantation 2007;84(3):362-

73. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Naesens M, De Loor H, Vanrenterghem Y, et al. The 

impact of renal allograft function on exposure and 

elimination of mycophenolic acid (MPA) and its metabolite 

MPA 7-O-glucuronide. Transplantation 2007;84(3):362-

73. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Naesens M, Verbeke K, Vanrenterghem Y, et al. Effects of 

gastric emptying on oral mycophenolic acid 

pharmacokinetics in stable renal allograft recipients. Br J 

Clin Pharmacol 2007;63(5):541-7. 

Excluded because not a full report of an included study 

type 

Nankivell BJ, Wavamunno MD, Borrows RJ, et al. 

Mycophenolate mofetil is associated with altered 

expression of chronic renal transplant histology. Am J 

Transplant 2007;7(2):366-76. 

Excluded because MPA not measured in blood 

Nanni G, Pisanti F, Navarra P, et al. Lack of correlation 

between serum levels of mycophenolate mofetil and kidney 

transplant outcome in tacrolimus-based immunosupression. 

Transplant Proc 2002;34(6):2085-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Narumi S, Hakamada K, Sasaki M, et al. Liver 

transplantation for autoimmune hepatitis: Rejection and 

recurrence. Transplant Proc 1999;31(5):1955-6. 
D-14

Excluded because MPA not measured in blood 

Neumann I, Haidinger M, Jager H, et al. Pharmacokinetics 

of mycophenolate mofetil in patients with autoimmune 

diseases compared renal transplant recipients. J Am Soc 

Nephrol 2003;14(3):721-7. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Ng KP, Cambridge G, Leandro MJ, et al. B cell depletion 

therapy in systemic lupus erythematosus: Long-term 

follow-up and predictors of response. Ann Rheum Dis 

2007; 66(9):1259-62. 

Excluded because does not report on humans with a solid 

organ transplant 

Nobili V, Comparcola D, Sartorelli MR, et al. 

Mycophenolate mofetil in pediatric liver transplant patients 

with renal dysfunction: preliminary data.[erratum appears 

in Pediatr Transplant. 2004 Feb;8(1): 94]. Pediatr 

Transplant 2003;7(6):454-7. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Nobili V, Comparcola D, Sartorelli MR, et al. Erratum: 

Mycophenolate mofetil in pediatric liver transplant patients 

with renal dysfunction: Preliminary data (Pediatric 

Transplantation (2003) 7 (454-457)). Pediatr Transplant 

2004;8(1):94 

Excluded because not a full report of an included study 

type 

Nogueira E, Ozaki KS, Tomiyama H, et al. The emergence 

of cytomegalovirus resistance to ganciclovir therapy in 

kidney transplant recipients. Int Immunopharmacol 

2006;6(13-14):2031-7. 

Excluded because MPA not measured in blood 

Nogueras F, Espinosa MD, Mansilla A, et al. 

Mycophenolate mofetil-induced neutropenia in liver 

transplantation. Transplant Proc 2005;37(3):1509-11. 

Excluded because not a full report of an included study 

type 

Novoa P, Rodriguez L, Gutierrez L. Report of the 

experience with enteric-coated sodium 

mycophenolate in a de novo population of kidney 

transplant recipients at high risk for 

delayed graft function. Transplant Proc 2007;39(3):600-1. 

Excluded because MPA not measured in blood 

Ogawa N, Nagashima N, Nakamura M, et al. Measurement 

of mycophenolate mofetil effect in transplant recipients. 

Transplantation 2001;72(3):422-7. 

Excluded because MPA not measured in blood 

Okusanya O, Dole K, Zack J, et al. Population 

pharmacokinetic (PK) model of mycophenolic acid (MPA) 

and its metabolite - Mycophenolic acid glucoronide 

(MPAG) in long term transplant renal patients using 

Montecarlo parametric expectation maximization (MCPEM). Clin Pharmacol Ther 2007;81(Suppl. 1): 

Excluded because not a full report of an included study 

type 

Oliveira JG, Sampaio S, Xavier P, et al. Cytokine analysis 

before and after mycophenolate mofetil treatment in renal 

transplantation. Transplant Proc 2000;32(8):2631-2. 

Excluded because MPA not measured in blood 

Ourahma S, Mercadal L, du Montcel ST, et al. Anemia in 

the Period Immediately Following Renal Transplantation. 

Transplant Proc 2007;39(5):1446-50. 

Excluded because MPA not measured in blood 

Pageaux G-P, Rostaing L, Calmus Y, et al. Mycophenolate 

mofetil in combination with reduction of calcineurin 

inhibitors for chronic renal dysfunction after liver 

transplantation. Liver Transpl 2006;12(12):1755-60. 

Excluded because MPA not measured in blood 

Papadea CN, Weimert N, Uber W. Mycophenolic acid 

assay by tandem mass spectrometry: Analytical and clinical 

experience for immunosuppression in organ 

transplantation. Ann Clin Lab Sci 2007;37(2) 

Excluded because not a full report of an included study 

type 

Pape L, Hoppe J, Becker T, et al. Superior long-term graft 

function and better growth of grafts in children receiving 

kidneys from paediatric compared with adult donors. 

Nephrol Dial Transplant 2006;21(9):2596-600. 

Excluded because MPA not measured in blood 

Pape L, Ahlenstiel T, Ehrich JHH, et al. Reversal of loss of 

glomerular filtration rate in children with transplant 

nephropathy after switch to everolimus and low-dose 

cyclosporine A. Pediatr Transplant 2007;11(3):291-5. 

Excluded because MPA not measured in blood 

Pareja-Ciuro F, Diez-Canedo JS, Gomez-Bravo MA, et al. 

Efficacy and safety of mycophenolate mofetil as part of 

induction therapy in liver transplantation. Transplant Proc 

2005;37(9):3926-9. 

Excluded because MPA not measured in blood 

Park SI, Felipe CR, Machado PG, et al. 

Pharmacokinetic/pharmacodynamic relationships of 

FTY720 in kidney transplant recipients. Braz J Med Biol 

Res 2005;38(5):683-94. 

Excluded because MPA not measured in blood 

Pascual M, Curtis J, Delmonico FL, et al. A prospective, 

randomized clinical trial of cyclosporine reduction in stable 

patients greater than 12 months after renal transplantation. 

Transplantation 2003;75(9):1501-5. 

Excluded because MPA not measured in blood 

Patel CG, Harmon M, Gohh RY, et al. Concentrations of 

mycophenolic acid and glucuronide metabolites under 

concomitant therapy with cyclosporine or tacrolimus. Ther 

Drug Monit 2007;29(1):87-95. 

Excluded because MPA levels not associated with any 

clinical outcomes 
D-15

Patel J, Kawano M, Wu G, et al. Practically speaking: The 

initiation of lower dose mycophenolate mofetil 

(MMF)1000 mg bid appears to have similar outcome to 

1500 mg bid after heart transplantation. J Heart Lung 

Transplant 2007;26(2, Suppl. S): 

Excluded because not a full report of an included study 

type 

Pawinski T, Hale M, Korecka M, et al. Limited sampling 

strategy for the estimation of mycophenolic acid area under 

the curve in adult renal transplant patients treated with 

concomitant tacrolimus. Clin Chem 2002;48(9):1497-504. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Payen S, Zhang D, Maisin A, et al. Population 

pharmacokinetics of mycophenolic acid in kidney 

transplant pediatric and adolescent patients. Ther Drug 

Monit 2005;27(3):378-88. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Pelletier RP, Soule J, Henry ML, et al. Clinical outcomes 

of renal transplant recipients 

treated with enteric-coated mycophenolic acid vs. 

mycophenolate mofetil as a switch agent 

using a primary steroid-free rapamune and microemulsion 

cyclosporine protocol. Clin Transplant 2007;21(4):532-5. 

Excluded because MPA not measured in blood 

Perkins JD. It matters to monitor drug levels. Liver Transpl 

2006;12(7):1169-70. 

Excluded because not a full report of an included study 

type 

Perrea DN, Moulakakis KG, Poulakou MV, et al. 

Correlation between oxidative stress and 

immunosuppressive therapy in renal transplant recipients 

with an uneventful postoperative course and stable renal 

function. Int Urol Nephrol 2006;38(2):343-8. 

Excluded because MPA not measured in blood 

Perry TW, Christians U, Trotter JF, et al. 

Pharmacokinetics of enteric-coated 

mycophenolate sodium in stable liver transplant recipients. 

Clin Transplant 2007;21(3):413-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Pescovitz MD, Conti D, Dunn J, et al. Intravenous 

mycophenolate mofetil: safety, 

tolerability, and pharmacokinetics. Clin Transplant 

2000;14(3):179-88. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Pescovitz MD, Barbeito R, Simulect US. Two-hour postdose cyclosporine level is a better predictor than trough 

level of acute rejection of renal allografts. Clin Transplant 

2002;16(5):378-82. 

Excluded because MPA not measured in blood 

Pescovitz MD, Guasch A, Gaston R, et al. Equivalent 

pharmacokinetics of mycophenolate mofetil in AfricanAmerican and Caucasian male and female stable renal 

allograft recipients.[erratum appears in Am J Transplant. 

2004 Nov;4(11):1928]. Am J Transplant 2003;3(12):1581-

6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Pescovitz MD, Bumgardner G, Gaston RS, et al. 

Pharmacokinetics of daclizumab and 

mycophenolate mofetil with cyclosporine and steroids in 

renal transplantation. Clin Transplant 2003;17(6):511-7. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Pethig K, Heublein B, Wahlers T, et al. Mycophenolate 

mofetil for secondary prevention of cardiac allograft 

vasculopathy: influence on inflammation and progression 

of intimal hyperplasia. J Heart Lung Transplant 

2004;23(1):61-6. 

Excluded because MPA not measured in blood 

Picard N, Cresteil T, Premaud A, et al. Characterization of 

a phase 1 metabolite of mycophenolic acid produced by 

CYP3A4/5. Ther Drug Monit 2004;26(6):600-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Picard N, Ratanasavanh D, Premaud A, et al. Identification 

of the UDP-glucuronosyltransferase isoforms involved in 

mycophenolic acid phase II metabolism. Drug Metab 

Dispos 2005;33(1):139-46. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Picard N, Premaud A, Rousseau A, et al. A comparison of 

the effect of ciclosporin and sirolimus on the 

pharmokinetics of mycophenolate in renal transplant 

patients. Br J Clin Pharmacol 2006;62(4):477-84. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Pieper AK, Buhle F, Bauer S, et al. The effect of 

sevelamer on the pharmacokinetics of cyclosporin A and 

mycophenolate mofetil after renal transplantation. 

Nephrol Dial Transplant 2004;19(10):2630-3. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Pietruck F, Budde K, Salvadori M, et al. Efficacy and 

safety of enteric-coated mycophenolate sodium in renal 

transplant patients with diabetes mellitus: post hoc 

analyses from three clinical trials. Clin Transplant 

2007;21(1):117-25. 

Excluded because MPA not measured in blood 

Pietruck F, Abbud-Filho M, Vathsala A, et al. Conversion 

from mycophenolate mofetil to enteric-coated 

mycophenolate sodium in stable maintenance renal 
D-16

transplant patients: pooled results from three international, 

multicenter studies. Transplant Proc 2007;39(1):103-8. 

Excluded because MPA not measured in blood 

Pirsch J, Bekersky I, Vincenti F, et al. Coadministration of 

tacrolimus and mycophenolate mofetil in stable kidney 

transplant patients: pharmacokinetics and tolerability. J 

Clin Pharmacol 2000;40(5):527-32. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Pisupati J, Jain A, Burckart G, et al. Intraindividual and 

interindividual variations in the pharmacokinetics of 

mycophenolic acid in liver transplant patients. J Clin 

Pharmacol 2005;45(1):34-41. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Pohanka E. Conversion to everolimus in maintenance 

patients--current clinical strategies. 

Nephrol Dial Transplant 2006;21:Suppl-9 

Excluded because not a full report of an included study 

type 

Pou L, Brunet M, Cantarell C, et al. Mycophenolic acid 

plasma concentrations: influence of comedication. Ther 

Drug Monit 2001;23(1):35-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Pourfarziani V, Panahi Y, Assari S, et al. Changing 

Treatment Protocol From Azathioprine to Mycophenolate 

Mofetil: Decrease in Renal Dysfunction, Increase in 

Infections. Transplant Proc 2007;39(4):1237-40. 

Excluded because MPA not measured in blood 

Premaud A, Rousseau A, Le Meur Y, et al. Comparison of 

liquid chromatography-tandem mass spectrometry with a 

commercial enzyme-multiplied immunoassay for the 

determination of plasma MPA in renal transplant recipients 

and consequences for therapeutic drug monitoring. Ther 

Drug Monit 2004;26(6):609-19. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Premaud A, Le Meur Y, Debord J, et al. Maximum a 

posteriori bayesian estimation of mycophenolic acid 

pharmacokinetics in renal transplant recipients at different 

postgrafting periods. Ther Drug Monit 2005;27(3):354-61. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Premaud A, Debord J, Rousseau A, et al. A double 

absorption-phase model adequately describes 

mycophenolic acid plasma profiles in de novo renal 

transplant recipients given 

oral mycophenolate mofetil. Clin Pharmacokinet 

2005;44(8):837-47. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Premaud A, Rousseau A, Picard N, et al. Determination of 

mycophenolic acid plasma levels in renal transplant 

recipients co-administered sirolimus: comparison of an 

enzyme multiplied immunoassay technique (EMIT) and 

liquid chromatography-tandem mass spectrometry. Ther 

Drug Monit 2006;28(2):274-7. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Remuzzi G, Cravedi P, Costantini M, et al. Mycophenolate 

mofetil versus azathioprine for prevention of chronic 

allograft dysfunction in renal transplantation: The MYSS 

follow-up randomized, controlled clinical trial. J Am Soc 

Nephrol 2007;18(6):1973-85. 

Excluded because MPA not measured in blood 

Remuzzi G, Perico N. Protecting single-kidney allografts 

from long-term functional deterioration. J Am Soc Nephrol 

1998;9(7):1321-32. 

Excluded because not a full report of an included study 

type 

Renders L, Steinbach R, Valerius T, et al. Low-dose 

sirolimus in combination with mycophenolate mofetil 

improves kidney graft function late after renal 

transplantation and suggests pharmacokinetic interaction of 

both immunosuppressive drugs. Kidney Blood Press Res 

2004;27(3):181-5. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Rerolle JP, Szelag JC, Le Meur Y. Unexpected rate of 

severe leucopenia with the association of mycophenolate 

mofetil and valganciclovir in kidney transplant recipients. 

Nephrol Dial Transplant 2007;22(2):671-2. 

Excluded because not a full report of an included study 

type 

Rial M, Guardia O, Greco G, et al. Area under the curve of 

Neoral and chronic use of mycophenolate mofetil. 

Yransplant Proc 1998;30(4):1195-6. 

Excluded because MPA not measured in blood 

Riechsteiner G, Speich R, Schanz U, et al. Haemolytic 

anaemia after lung transplantation: an immune-mediated 

phenomenon? Swiss Medical Weekly 2003;133(9-10):143-

7. 

Excluded because MPA not measured in blood 

Rigotti P, European Tacrolimus/MMF Transplantation 

Study Group. Patients with high cholesterol levels benefit 

most from early withdrawal of corticosteroids. Transplant 

Proc 2002;34(5):1797-8. 

Excluded because MPA not measured in blood 

Rippin SJ, Serra AL, Marti HP, et al. Six-year follow-up of 

azathioprine and mycophenolate mofetil use during the first 

6 months of renal transplantation. Clin Nephrol 

2007;67(6):374-80. 

Excluded because MPA not measured in blood 
D-17

Rose ML, Smith J, Dureau G, et al. Mycophenolate mofetil 

decreases antibody production after cardiac transplantation. 

J Heart Lung Transplant 2002;21(2):282-5. 

Excluded because MPA not measured in blood 

Ruiz JC, Sanchez-Fructuoso A, Rodrigo E, et al. 

Conversion to Everolimus in Kidney Transplant Recipients: 

A Safe and Simple Procedure. Transplant Proc 

2006;38(8):2424-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Saito K, Nakagawa Y, Suwa M, et al. Pinpoint targeted 

immunosuppression: anti-CD20/MMF desensitization with 

anti-CD25 in successful ABO-incompatible kidney 

transplantation without splenectomy. Xenotransplantation 

2006;13(2):111-7. 

Excluded because not a full report of an included study 

type 

Saliba F, Lakehal M, Pageaux G-P, et al. Risk factors for 

new-onset diabetes mellitus following liver transplantation 

and impact of hepatitis C infection: An observational 

multicenter study. Liver Transpl 2007;13(1):136-44. 

Excluded because MPA not measured in blood 

Sanchez FA, Calvo N, Moreno MA, et al. Better 

mycophenolic Acid 12-hour trough level 

after enteric-coated mycophenolate sodium in patients with 

gastrointestinal intolerance to 

mycophenolate mofetil. Transplant Proc 2007;39(7):2194-

6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Sanquer S, Breil M, Baron C, et al. Trough blood 

concentrations in long-term treatment with mycophenolate 

mofetil. Lancet 1998;351(9115):1557 

Excluded because not a full report of an included study 

type 

Sanquer S, Breil M, Baron C, et al. Induction of inosine 

monophosphate dehydrogenase activity after long-term 

treatment with mycophenolate mofetil. Clin Pharmacol 

Ther 1999;65(6):640-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Schachter AD, Meyers KE, Spaneas LD, et al. Short 

sirolimus half-life in pediatric renal transplant recipients on 

a calcineurin inhibitor-free protocol. Pediatr Transplant 

2004;8(2):171-7. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Schaefer HM, Kizilisik AT, Feurer I, et al. Short-term 

Results Under Three Different Immunosuppressive 

Regimens at One Center. Transplant Proc 

2006;38(10):3466-7. 

Excluded because MPA not measured in blood 

Schlavelli R, Gaite L, Carreno C, et al. Use of entericcoated mycophenolate sodium in de novo renal transplant 

recipients with high incidence of delayed graft function. 

Transplant Proc 2006;38(5):905 

Excluded because MPA not measured in blood 

Schlitt HJ, Barkmann A, Boker KH, et al. Replacement of 

calcineurin inhibitors with mycophenolate mofetil in livertransplant patients with renal dysfunction: a randomised 

controlled study. Lancet 2001;357(9256):587-91. 

Excluded because MPA not measured in blood 

Schmidt LE, Rasmussen A, Norrelykke MR, et al. The 

effect of selective bowel decontamination on the 

pharmacokinetics of mycophenolate mofetil in liver 

transplant recipients. Liver Transpl 2001;7(8):739-42. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Schutz E, Armstrong VW, Shipkova M, et al. Limited 

sampling strategy for the determination of mycophenolic 

acid area under the curve in pediatric kidney recipients. 

German Study Group on MMF Therapy in Pediatric Renal 

Transplant Recipients. Transplant Proc 1998;30(4):1182-4. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Schutz E, Shipkova M, Armstrong VW, et al. Therapeutic 

drug monitoring of mycophenolic acid: comparison of 

HPLC and immunoassay reveals new MPA metabolites. 

Transplant Proc 1998;30(4):1185-7. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Schutz E, Shipkova M, Armstrong VW, et al. 

Identification of a pharmacologically active metabolite of 

mycophenolic acid in plasma of transplant recipients 

treated with mycophenolate mofetil. Clin Chem 

1999;45(3):419-22. 

Excluded because not a full report of an included study 

type 

Schweiger M, Wasler A, Prenner G, et al. Everolimus and 

reduced cyclosporine trough levels in maintenance heart 

transplant recipients. Transpl Immunol 2006;16(1):46-51. 

Excluded because MPA not measured in blood 

Schweitzer EJ, Yoon S, Fink J, et al. Mycophenolate 

mofetil reduces the risk of acute rejection less in AfricanAmerican than in Caucasian kidney recipients. 

Transplantation 1998;65(2):242-8. 

Excluded because MPA not measured in blood 

Seebacher G, Mallinger R, Laufer G, et al. 

Pharmacokinetics of mycophenolate mofetil in heart 

transplant recipients. Adv Exp Med Biol 1998;431:801-3. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Seipelt IM, Crawford SE, Rodgers S, et al. 

Hypercholesterolemia is common after pediatric heart 
D-18

transplantation: initial experience with pravastatin. J Heart 

Lung Transplant 2004;23(3):317-22. 

Excluded because MPA not measured in blood 

Seron D. Is halving ciclosporin dose and introducing 

mycophenolate beneficial in chronic renal allograft 

dysfunction? Nat Clin Pract Nephrol 2007;3(4):198-9. 

Excluded because not a full report of an included study 

type 

Shaw LM. Mycophenolate mofetil: pharmacokinetic 

strategies for optimizing immunosuppression. Drug 

Metabol Drug Interact 1997;14(1):33-40. 

Excluded because not a full report of an included study 

type 

Sheashaa HA, Bakr MA, Fouda MA, et al. Is it worth 

using daclizumab induction therapy with mycophenolate 

mofetil-based immunosuppressive regimens in live related 

donor kidney transplantation? A long-term follow up. Int 

Urol Nephrol 2007;39(1):317-9. 

Excluded because MPA not measured in blood 

Shi Y, Moriyama T, Namba Y, et al. Association of 

treatment with 15-deoxyspergualin and BK virus 

nephropathy in kidney allograft recipients. Clin Transplant 

2007;21(4):502-9. 

Excluded because MPA not measured in blood 

Shipkova M, Armstrong VW, Schneider T, et al. Stability 

of mycophenolic acid and 

mycophenolic acid glucuronide in human plasma. Clin 

Chem 1999;45(1):127-9. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Shipkova M, Armstrong VW, Kuypers D, et al. Effect of 

cyclosporine withdrawal on mycophenolic acid 

pharmacokinetics in kidney transplant recipients with 

deteriorating 

renal function: preliminary report. Ther Drug Monit 

2001;23(6):717-21. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Shipkova M, Armstrong VW, Kiehl MG, et al. 

Quantification of mycophenolic acid in plasma samples 

collected during and immediately after intravenous 

administration of mycophenolate mofetil. Clin Chem 

2001;47(8):1485-8. 

Excluded because not a full report of an included study 

type 

Shipkova M, Armstrong VW, Weber L, et al. 

Pharmacokinetics and protein adduct formation of the 

pharmacologically active acyl glucuronide metabolite of 

mycophenolic acid in pediatric renal transplant recipients. 

Ther Drug Monit 2002;24(3):390-9. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Shiroki R, Hoshinaga K, Higuchi T, et al. Analysis of the 

effects of recipient age and pretransplant hemodialysis 

period on cadaveric kidney transplant outcome using 

non-heart-beating donors. Transplant Proc 1999;31(5): 

1970-2. 

Excluded because MPA not measured in blood 

Shum B, Duffull SB, Taylor PJ, et al. Population 

pharmacokinetic analysis of mycophenolic acid in renal 

transplant recipients following oral administration of 

mycophenolate mofetil. Br J Clin Pharmacol 

2003;56(2):188-97. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Sievers TM, Holt CD, Ghobrial RM, et al. 

Pharmacokinetics of mycophenolic acid and clinical 

outcomes in liver transplant recepients with hepatitis C 

(HCV). Am J Transplant 2004;4(Suppl 8):365, 2004. 

Excluded because not a full report of an included study 

type 

Silva LA, Felipe CR, Park SI, et al. Impact of initial 

exposure to calcineurin inhibitors on kidney graft function 

of patients at high risk to develop delayed graft function. 

Braz J Med Biol Res 2006;39(1):43-52. 

Excluded because MPA not measured in blood 

Sindhi R, Magill A, Manavalan S, et al. Peripheral 

lymphocyte markers as surrogate measures of 

immunosuppression and post-transplant clinical states. 

Clinical & Applied Immunology Reviews 2004;4(4):225-

38. 

Excluded because not a full report of an included study 

type 

Smak Gregoor PJ, van Gelder T, Hesse CJ, et al. 

Mycophenolic acid plasma concentrations in kidney 

allograft recipients with or without cyclosporin: a crosssectional study. Nephrol Dial Transplant 1999;14(3):706-

8. 

Excluded because not a full report of an included study 

type 

Squifflet JP, Vanrenterghem Y, Van Hooff JP, et al. Safe 

withdrawal of corticosteroids or mycophenolate mofetil: 

results of a large, prospective, multicenter, randomized 

study. Transplant Proc 2002;34(5):1584-6. 

Excluded because MPA not measured in blood 

Srinivas TR, Schold JD, Guerra G, et al. Mycophenolate 

mofetil/sirolimus compared to other common 

immunosuppressive regimens in kidney transplantation. 

Am J Transplant 2007;7(3):586-94. 

Excluded because MPA not measured in blood 

Staatz CE, Duffull SB, Kiberd B, et al. Population 

pharmacokinetics of mycophenolic acid during the first 

week after renal transplantation. Eur J Clin Pharmacol 

2005;61(7):507-16. 

Excluded because MPA levels not associated with any 

clinical outcomes 
D-19

Stalder M, Birsan T, Holm B, et al. Quantification of 

immunosuppression by flow cytometry in stable renal 

transplant recipients. Ther Drug Monit 2003;25(1):22-7. 

Excluded because MPA not measured in blood 

Stratta RJ, Sundberg AK, Farney AC, et al. Experience 

with alternate-day thymoglobulin induction in pancreas 

transplantation with portal-enteric drainage. Transplant 

Proc 2005;37(8):3546-8. 

Excluded because MPA not measured in blood 

Subbanna PK, Prasanna CG, Gunale BK. Investigation on 

pharmacokinetics of mycophenolic acid in Chinese adult 

renal transplant patients [1]. Br J Clin Pharmacol 

2007;64(2):245 

Excluded because not a full report of an included study 

type 

Sudchada P, Dole K, Zack J, et al. Influence of race and 

steroid use on mycophenolic acid 

pharmacokinetics post-renaltransplant. Clin Pharmacol 

Ther 2007;81(Suppl. 1): 

Excluded because not a full report of an included study 

type 

Sumethkul V, Changsirikulchai S, Lothuvachai T, et al. 

Sirolimus Attenuates the Rate of Progression of Early 

Chronic Allograft Nephropathy. Transplant Proc 

2006;38(10):3470-2. 

Excluded because MPA not measured in blood 

Sun Q, Liu Z-H, Chen J, et al. An aggressive systematic 

strategy for acute respiratory 

distress syndrome caused by severe pneumonia after renal 

transplantation. Transpl Int 2006;19(2):110-6. 

Excluded because MPA not measured in blood 

Sun Q, Liu Z-H, Cheng Z, et al. Treatment of early mixed 

cellular and humoral renal 

allograft rejection with tacrolimus and mycophenolate 

mofetil. Kidney Int 2007;71(1):24-30. 

Excluded because MPA not measured in blood 

Suntornsuk L, Meyer T, Lindgren A, et al. A micellar 

electrokinetic capillary 

chromatography method for monitoring mycophenolic acid 

in serum of transplant recipients. Pharmazie 

2005;60(2):115-9. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Suwelack B, Gerhardt U, Kobelt V, et al. Design and 

preliminary results of a randomized study on the 

conversion of treatment with calcineurin inhibitors to 

mycophenolate mofetil 

in chronic renal graft failure: effect, on serum cholesterol 

levels. Transplant Proc 2002;34(5):1803-5. 

Excluded because MPA not measured in blood 

Suwelack B, Kobelt V, Hillebrand U, et al. Replacement of 

calcineurin inhibitors by 

mycophenolate mofetil: effect on hemoglobine levels. 

Transplant Proc 2002;34(5):1808-9. 

Excluded because MPA not measured in blood 

Szwarc I, Argiles A, Garrigue V, et al. Cinacalcet chloride 

is efficient and safe in renal transplant recipients with 

posttransplant hyperparathyroidism. Transplantation 

2006;82(5):675-80. 

Excluded because MPA not measured in blood 

Takami A, Mochizuki K, Okumura H, et al. 

Mycophenolate mofetil is effective and well tolerated in the 

treatment of refractory acute and chronic graft-versus-host 

disease. Int J Hematol 2006;83(1):80-5. 

Excluded because does not report on humans with a solid 

organ transplant 

Takekuma Y, Kakiuchi H, Yamazaki K, et al. Difference 

between pharmacokinetics of mycophenolic acid (MPA) in 

rats and that in humans is caused by different affinities of 

MRP2 to a glucuronized form. J Pharm Pharm Sci 

2007;10(1):71-85. 

Excluded because does not report on humans with a solid 

organ transplant 

Tamajon LP, Miranda DM, Figueroa AC, et al. Improved 

cardiovascular risk profile of patients with type 1 diabetes 

mellitus and renal failure after simultaneous pancreaskidney transplantation. Transplant Proc 2005;37(9):3979-

80. 

Excluded because MPA not measured in blood 

Tannuri U, Gibelli NEM, Maksoud-Filho JG, et al. 

Mycophenolate mofetil promotes prolonged improvement 

of renal dysfunction after pediatric liver transplantation: 

Experience of a single center. Pediatr Transplant 2007; 

11(1):82-6. 

Excluded because MPA not measured in blood 

Tedesco-Silva H, Mourad G, Kahan BD, et al. FTY720, a 

novel immunomodulator: efficacy and safety results from 

the first phase 2A study in de novo renal transplantation. 

[republished in Transplantation. 2005 Jun 15;79(11):1553-

60; PMID: 15940045]. Transplantation 2004;77(12):1826-

33. 

Excluded because MPA not measured in blood 

Tedesco-Silva H, Bastien MC, Choi L, et al. 

Mycophenolic acid metabolite profile in renal transplant 

patients receiving enteric-coated mycophenolate sodium or 

mycophenolate mofetil. Transplant Proc 2005;37(2):852-5. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Tedesco-Silva H, Pescovitz MD, Cibrik D, et al. 

Randomized controlled trial of FTY720 versus MMF in de 

novo renal transplantation. Transplantation 2006;82(12): 

1689-97. 

Excluded because MPA not measured in blood 

Tedoriya T, Keogh AM, Kusano K, et al. Reversal of 

chronic cyclosporine nephrotoxicity after heart 
D-20

transplantation-potential role of mycophenolate mofetil. J 

Heart Lung Transplant 2002;21(9):976-82. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Teebken OE, Struber M, Harringer W, et al. Primary 

immunosuppression with tacrolimus and mycophenolate 

mofetil versus cyclosporine and azathioprine in heart 

transplant recipients. Transplant Proc 2002;34(4):1265-8. 

Excluded because MPA not measured in blood 

Ting LS, Partovi N, Levy RD, et al. Pharmacokinetics of 

mycophenolic acid and its glucuronidated metabolites in 

stable lung transplant recipients. Ann Pharmacother 

2006;40(9):1509-16. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Ting LS, Decarie D, Ensom MH. Effect of acidification on 

protein binding of mycophenolic 

acid. Ther Drug Monit 2007;29(1):132-3. 

Excluded because not a full report of an included study 

type 

Ting LSL, Partovi N, Levy RD, et al. Limited sampling 

strategy for predicting area under the concentration-time 

curve of mycophenolic acid in adult lung transplant 

recipients. 

Pharmacotherapy 2006;26(9 I):1232-40. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Tripodi V, Nunez M, Carducci C, et al. Total serum bile 

acids in renal transplanted patients receiving cyclosporine 

A. Clin Nephrol 2002;58(5):350-5. 

Excluded because MPA not measured in blood 

Trivedi H, Vanikar A, V, Modi P, et al. Allogeneic 

hematopoietic stem-cell 

transplantation, mixed chimerism, and tolerance in living 

related donor renal allograft 

recipients. Transplant Proc 2005;37(2):737-42. 

Excluded because MPA not measured in blood 

Tsai MK, Lee CY, Hu RH, et al. Conversion to combined 

therapy with sirolimus and mycophenolate mofetil 

improved renal function in stable renal transplant 

recipients. J 

Formos Med Assoc 2007;106(5):372-9. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Undre NA, van Hooff J, Christiaans M, et al. 

Pharmacokinetics of FK 506 and mycophenolic acid after 

the administration of a FK 506-based regimen in 

combination with mycophenolate mofetil in kidney 

transplantation. Transplant Proc 1998;30(4):1299-302. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Unsalan S, Hempel G, Fobker M, et al. Monitoring of 

mycophenolic acid in the plasma of 

transplant patients by capillary electrophoresis. 

Chromatographia 2006;64(7-8):419-21. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Uwai Y, Motohashi H, Tsuji Y, et al. Interaction and 

transport characteristics of mycophenolic acid and its 

glucuronide via human organic anion transporters hOAT1 

and hOAT3. Biochem Pharmacol 2007;74(1):161-8. 

Excluded because does not report on humans with a solid 

organ transplant 

van Besouw NM, Van Der Mast BJ, de Kuiper P, et al. 

Down-regulated donor-specific T-cell reactivity during 

successful tapering of immunosuppression after kidney 

transplantation. Clin Exp Immunol 2002;128(2):388-93. 

Excluded because MPA not measured in blood 

Van Der Mast BJ, van Besouw NM, Witvliet MD, et al. 

Formation of donor-specific human leukocyte antigen 

antibodies after kidney transplantation: correlation with 

acute rejection and tapering of immunosuppression. 

Transplantation 2003;75(6):871-7. 

Excluded because MPA not measured in blood 

Van Hest R, Mathot R, Vulto A, et al. Predicting the 

usefulness of therapeutic drug monitoring of mycophenolic 

acid: a computer simulation. Ther Drug Monit 

2005;27(2):163-7. 

Excluded because not a full report of an included study 

type 

Van Hest RM, Mathot RA, Vulto AG, et al. Mycophenolic 

acid in diabetic renal transplant recipients: 

pharmacokinetics and application of a limited sampling 

strategy. Ther Drug Monit 2004;26(6):620-5. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Van Hest RM, van Gelder T, Vulto AG, et al. Population 

pharmacokinetics of mycophenolic acid in renal transplant 

recipients. Clin Pharmacokinet 2005;44(10):1083-96. 

Excluded because MPA levels not associated with any 

clinical outcomes 

van Hest RM, van Gelder T, Bouw R, et al. Timedependent clearance of mycophenolic acid in renal 

transplant recipients. Br J Clin Pharmacol 2007;63(6):741-

52. 

Excluded because MPA levels not associated with any 

clinical outcomes 

van Hest RM, Doorduijn JK, de Winter BC, et al. 

Pharmacokinetics of mycophenolate mofetil in 

hematopoietic stem cell transplant recipients. Ther Drug 

Monit 2007;29(3):353-60. 

Excluded because does not report on humans with a solid 

organ transplant 

Vannozzi F, Filipponi F, Di Paolo A, et al. An exploratory 

study on pharmacogenetics of inosine-monophosphate 

dehydrogenase II in peripheral mononuclear cells from 
D-21

liver-transplant recipients. Transplant Proc 

2004;36(9):2787-90. 

Excluded because MPA not measured in blood 

Velthuis JHL, Mol WM, Weimar W, et al. 

CD4<sup>+</sup> CD25<sup>bright+</sup> regulatory T 

cells can mediate donor nonreactivity in long-term 

immunosuppressed kidney allograft patients. Am J 

Transplant 2006;6(12):2955-64. 

Excluded because MPA not measured in blood 

Vessal G, Wiland AM, Philosophe B, et al. Early steroid 

withdrawal in solitary pancreas transplantation results in 

equivalent graft and patient survival compared with 

maintenance steroid therapy. Clin Transplant 

2007;21(4):491-7. 

Excluded because MPA not measured in blood 

Vethe NT, Mandla R, Line PD, et al. Inosine 

monophosphate dehydrogenase activity in renal allograft 

recipients during mycophenolate treatment. Scan J Clin 

Lab Invest 2006;66(1):31-44. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Vidal E, Cantarell C, Capdevila L, et al. Mycophenolate 

mofetil pharmacokinetics in transplant patients receiving 

cyclosporine or tacrolimus in combination therapy. 

Pharmacology and Toxicology 2000;87(4):182-4. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Videla C, Godoy C. Converting to a generic formulation of 

mycophenolate mofetil in stable kidney transplant 

recipients: 1 year of drug surveillance and outcome. 

Transplant Proc 2007;39(3):602-5. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Vietri M, Pietrabissa A, Mosca F, et al. Inhibition of 

mycophenolic acid glucuronidation by niflumic acid in 

human liver microsomes. Eur J Clin Pharmacol 

2002;58(2):93-7. 

Excluded because does not report on humans with a solid 

organ transplant 

Wada K, Takada M, Ueda T, et al. Pharmacokinetic study 

and limited sampling strategy of cyclosporine in Japanese 

heart transplant recipients. Circ J 2006;70(10):1307-11. 

Excluded because MPA not measured in blood 

Wada K, Takada M, Ueda T, et al. Relationship between 

acute rejection and cyclosporine or mycophenolic acid 

levels in Japanese heart transplantation. Circ J 

2007;71(3):289-93. 

Excluded because not a full report of an included study 

type 

Wada K, Takada M, Kotake T, et al. Limited sampling 

strategy for mycophenolic acid in Japanese heart transplant 

recipients: comparison of cyclosporin and tacrolimus 

treatment. Circ J 2007;71(7):1022-8. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Wada K, Kato T, Oda N, et al. Therapeutic monitoring of 

mycophenolate mofetile dose by twelve-hour-area under 

the curve to avoid acute rejection in heart transplant 

recipients. J Heart Lung Transplant 2007;26(2, Suppl. S): 

Excluded because not a full report of an included study 

type 

Wang J, Zeevi A, Webber S, et al. IMPDH2 and 

mycophenolic acid: Effect of a novel SNP on enzyme 

activity and leukopenia in transplant patients. J Clin 

Pharmacol 2006;46(9): 

Excluded because not a full report of an included study 

type 

Wang W. A pilot trial with pig-to-man islet transplantation 

at the 3rd Xiang-Ya Hospital of the Central South 

University in Changsha. Xenotransplantation 

2007;14(4):358 

Excluded because MPA not measured in blood 

Wang XH, Tang XD, Xu D. Tacrolimus vs CyA Neoral in 

combination with MMF and steroids after cadaveric renal 

transplantation. Transplant Proc 2000;32(7):1702-3. 

Excluded because MPA not measured in blood 

Wawrzynowicz-Syczewska M, Herman E, Jurczyk K, et al. 

Does cyclosporine inhibit in vivo hepatitis C virus 

replication? - A pilot study [1]. Transpl Int 2007;20(9): 

808-10. 

Excluded because MPA not measured in blood 

Weber LT, Schutz E, Lamersdorf T, et al. 

Pharmacokinetics of mycophenolic acid (MPA) and free 

MPA in paediatric renal transplant recipients - A 

multicentre study. Nephrol Dial Transplant 

1999;14(SUPPL.4):33-4. 

Excluded because not a full report of an included study 

type 

Weber LT, Schutz E, Lamersdorf T, et al. Therapeutic 

drug monitoring of total and free mycophenolic acid 

(MPA) and limited sampling strategy for determination of 

MPA-AUC in paediatric renal transplant recipients. 

Nephrol Dials Transplant 1999;14(SUPPL. 4):34-5. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Weigel G, Griesmacher A, Zuckermann AO, et al. Effect 

of mycophenolate mofetil therapy on inosine 

monophosphate dehydrogenase induction in red blood cells 

of heart transplant recipients. Clin Pharmacol Ther 

2001;69(3):137-44. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Weigel G, Griesmacher A, Karimi A, et al. Effect of 

mycophenolate mofetil therapy on lymphocyte activation in 

heart transplant recipients. J Heart Lung Transplant 

2002;21(10):1074-9. 
D-22

Excluded because MPA not measured in blood 

Weimer R, Streller S, Staak A, et al. Effects of three 

immunosuppressive regimens on CD4 helper function, B 

cell monocyte and cytokine responses in renal transplant 

recipients: 4-month follow-up of a prospective randomized 

study. Transplant Proc 2002;34(6):2377-8. 

Excluded because MPA not measured in blood 

Weimer R, Mytilineos J, Feustel A, et al. Mycophenolate 

mofetil-based immunosuppression and cytokine genotypes: 

effects on monokine secretion and antigen presentation in 

long-term renal transplant recipients. Transplantation 

2003;75(12):2090-9. 

Excluded because MPA not measured in blood 

Weimer R, Susal C, Yildiz S, et al. sCD30 and neopterin 

as risk factors of chronic renal 

transplant rejection: impact of cyclosporine A, tacrolimus, 

and mycophenolate mofetil. 

Transplant Proc 2005;37(4):1776-8. 

Excluded because MPA not measured in blood 

Westley IS, Ray JE, Morris RG. CEDIA mycophenolic 

acid assay compared with HPLC-UV in specimens from 

transplant recipients. Ther Drug Monit 2006;28(5):632-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Wierzbicka A, Pawlowska J, Socha P, et al. Lipid, 

Carbohydrate Metabolism, and Antioxidant Status in 

Children After Liver Transplantation. Transplant Proc 

2007; 

39(5):1523-5. 

Excluded because MPA not measured in blood 

Wiesner RH, Steffen BJ, David KM, et al. Mycophenolate 

mofetil use is associated with decreased risk of late acute 

rejection in adult liver transplant recipients. Am J 

Transplant 2006;6(7):1609-16. 

Excluded because MPA not measured in blood 

Wigger M, Armstrong VW, Shipkova M, et al. Atypical 

pharmacokinetics and metabolism of mycophenolic acid in 

a young kidney transplant recipient with impaired renal 

function. 

Ther Drug Monit 2002;24(3):438-43. 

Excluded because not a full report of an included study 

type 

Winkelmayer WC, Kewalramani R, Rutstein M, et al. 

Pharmacoepidemiology of anemia in kidney transplant 

recipients. J Am Soc Nephrol 2004;15(5):1347-52. 

Excluded because MPA not measured in blood 

Wlodarczyk Z, Walaszewski J, Perner F, et al. Freedom 

from rejection and stable kidney function are excellent 

criteria for steroid withdrawal in tacrolimus-treated kidney 

transplant recipients. Ann Transplant 2002;7(3):28-31. 

Excluded because MPA not measured in blood 

Wong BM, Huang M, Zaltzman JS, et al. Mycophenolate 

mofetil and c-reactive protein in renal transplant recipients. 

Transplantation 2007;83(1):48-53. 

Excluded because MPA not measured in blood 

Xia D, Yan L-N, Xu L, et al. Postoperative Severe 

Pneumonia in Adult Liver Transplant Recipients. 

Transplant Proc 2006;38(9):2974-8. 

Excluded because MPA not measured in blood 

Yeung S, Tong KL, Tsang WK, et al. Pharmacokinetic 

study of mycophenolate mofetil in Asian renal transplant 

recipients. Transplant Proc 2000;32(7):1753-4. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Yeung S, Tsang WK, Tong KL, et al. Primary 

immunosuppression with tacrolimus and low-dose 

mycophenolate mofetil in renal transplant recipients. 

Transplant Proc 2004;36(7):2084-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Yin J, Wang S, Yang G, et al. Molecularly imprinted solidphase extraction for rapid screening of mycophenolic acid 

in human plasma. J Chromatogr B 2006;844(1):142-7. 

Excluded because does not report on humans with a solid 

organ transplant 

Ying C, Colonno R, De Clercq E, et al. Ribavirin and 

mycophenolic acid markedly potentiate the anti-hepatitis B 

virus activity of entecavir. Antiviral Res 2007;73(3):192-6. 

Excluded because does not report on humans with a solid 

organ transplant 

Yorgin PD, Scandling JD, Belson A, et al. Late posttransplant anemia in adult renal transplant recipients. An 

under-recognized problem? Am J Transplant 

2002;2(5):429-35. 

Excluded because MPA not measured in blood 

Yu L, Wang Y, Fu SJ, et al. Clinical experience with 

Prograf (tacrolimus, FK 506) in Chinese patients after renal 

transplantation. Transplant Proc 2000;32(7):1709-10. 

Excluded because MPA not measured in blood 

Zanker B, Sohr B, Eder M, et al. Comparison of MPA 

trough levels in patients with severe diabetes mellitus and 

from non-diabetics after transplantation. Transplant Proc 

31(1-2):1167. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Zanker B, Schleibner S, Schneeberger H, et al. 

Mycophenolate mofetil in patients with acute renal failure: 

evidence of metabolite (MPAG) accumulation and removal 

by dialysis. Transpl Int 1996;9:Suppl-10 

Excluded because MPA levels not associated with any 

clinical outcomes 

Zhou PJ, Xu D, Yu ZC, et al. Pharmacokinetics of 

mycophenolic acid and estimation of exposure using 
D-23

multiple linear regression equations in Chinese renal 

allograft recipients. Clin Pharmacokinet 2007;46(5):389-

401. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Zicheng Y, Peijun Z, Da X, et al. Investigation on 

pharmacokinetics of mycophenolic acid in Chinese adult 

renal transplant patients. Br J Clin Pharmacol 

2006;62(4):446-52. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Zicheng Y, Weixia Z, Hao C, et al. Limited sampling 

strategy for the estimation of mycophenolic acid area under 

the plasma concentration-time curve in adult patients 

undergoing liver transplant. Ther Drug Monit 

2007;29(2):207-14. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Zicheng Y, Xianghui W, Peijun Z, et al. Evaluation of the 

practicability of limited sampling strategies for the 

estimation of mycophenolic acid exposure in Chinese adult 

renal recipients. Ther Drug Monit 2007;29(5):600-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 

Zucker K, Rosen A, Tsaroucha A, et al. Augmentation of 

mycophenolate mofetil pharmacokinetics in renal 

transplant patients receiving Prograf and CellCept in 

combination therapy. Transplant Proc 1997;29(1-2):334-6. 

Excluded because MPA levels not associated with any 

clinical outcomes 
E-1

Appendix E. Technical Expert Panel and Peer 

Reviewers

Members of the Technical Expert Panel (TEP) 

Prof. Dr. Klemens Budde 

Med. Klinik m.S. Nephrologie 

Charité Universitätsmedizin Berlin 

Germany 

Dr. Guido Filler 

Chair/Chief, Department of Paediatrics 

Children's Hospital of Western Ontario 

University of Western Ontario 

London, ON, Canada 

Dr. Maria Shipkova 

Zentralinstitut für Klinische Chemie 

und Laboratoriumsmedizin 

Klinikum Stuttgart 

Katharinenhospital 

Stuttgart, Germany 

Dr. Leslie M. Shaw 

Professor and Director 

Clinical Toxicology Laboratory 

Director 

Xenobiotic Toxicokinetics Research Laboratory 

University of Pennsylvania Medical Center 

Philadelphia, PA, USA 

Dr. Atholl Johnston 

Professor of Clinical Pharmacology 

Barts and The London Charterhouse Square 

London, UK 
E-2

Peer Reviewers of the Report 

Dr. Susan Maynard 

Department of Chemistry, Toxicology, and Blood Gases 

Carolinas Medical Center 

Charlotte, North Carolina, USA 

Dr. Robert H. Christenson 

Professor of Pathology & Medical and Research Technology 

Maryland School of Medicine 

Baltimore, MD, USA 

Prof. Dr. Klemens Budde 

Med. Klinik m.S. Nephrologie 

Charité Universitätsmedizin Berlin 

Germany 

Dr. Maria Shipkova 

Zentralinstitut für Klinische Chemie 

und Laboratoriumsmedizin 

Klinikum Stuttgart 

Katharinenhospital 

Stuttgart, Germany 

Dr. Michael Oellrich 

Director Department of Clinical Chemistry 

Georg-August Universitat 

Gottingen, Germany 

Dr. Darin Treleaven 

Department of Nephrology 

St. Joseph’s Healthcare 

Hamilton, ON, Canada 

Dr. Teun van Gelder 

Renal Transplant Unit and Clinical Pharmacology Unit 

Erasmus Medical Center 

Rotterdam, The Netherlands 

Dr. David W Holt 

Clinical Toxicology Department of Cardiological Sciences 

St. George’s Hospital 

London, ON, Canada