Conditions: Kidney Transplantation
Keywords: Kidney Immunosuppression Transplant
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
Tacrolimus extended release (Astagraf) has recently been approved by the FDA as a once a day dosing regimen. This formulation has the potential to improve compliance. Current dosing recommendation for the extended release formulation in renal transplant is 0.15 mg/kg/day administered once daily in the morning. There are no specifications on appropriate dosing in obese patients or on whether to use actual, ideal or and adjusted weight. It will be advantageous to understand the pharmacokinetics of this medication in the obese to determine the appropriate dosing regimen. In this study, obese patients will be randomized to receive tacrolimus extended release 0.15 mg/kg/day based on either ideal body weight (IBW) or adjusted body weight (aBW).

Detailed description:
Tacrolimus exhibits significant inter- and intra-individual variability of its absorption and metabolism. Because of this variability, standard dosing is not an accurate predictor of drug exposure. In clinical use, tacrolimus whole blood trough concentrations are measured to ensure efficacy and safety. Furthermore, the relatively low bioavailability of tacrolimus is thought to be a result of the combination of poor water-solubility, pre-systemic metabolism of tacrolimus in the gastrointestinal tract and activity of the P-glycoprotein efflux pump found in the enterocytes of the GI tract. Tacrolimus is extensively metabolized by the cytochrome P-450 system (CYP3A). The plasma protein binding of tacrolimus is approximately 99%. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein. The distribution of tacrolimus between blood and plasma depends on several factors including hematocrit, temperature at the time of plasma separation, drug concentration, and plasma protein concentration.

Pharmacodynamic studies have revealed that, depending on time following transplantation, maintaining whole blood trough levels between 5 and 20 ng/mL provides adequate protection against acute rejection and limits the occurrence of adverse events. The management of tacrolimus blood levels is complicated by variable intra- and inter-patient absorption, interaction with food and concomitant medications, and the relatively low bioavailability of tacrolimus from the Prograf formulation (17 ± 10% in adult kidney transplant patients).

Previous studies examining immunosuppressants have shown that drug levels in the immediate post-transplant period are a major determinant of subsequent acute cellular rejection. It is known that tacrolimus (TAC) \< 10 ng/mL is associated with increased rates of acute cellular rejection by one month post-transplant.

There is controversy regarding the appropriate dosing weight to use for immunosuppressants (IS). Weights use range from ideal body weight (IBW) to total body weight (TBW) depending on the institution and drug being dosed. This becomes particularly important in the obese population when there are significant differences between IBW and TBW. Our institution has always used IBW for the dosing of all IS due to concerns for nephrotoxicity with initial high blood levels of tacrolimus. The concern in obese patients is that the investigators are underdosing this population that could be at higher risk for rejection due to higher circulating concentrations of pro-inflammatory cytokines. The introduction of the novel use of a robotic transplantation procedure at our institution for this patient population has led to increasing numbers of transplant in obese recipients; therefore, the investigators decided to re-evaluate our dosing protocol. Data from an internal study at UIC show that our use of IBW for tacrolimus dosing is not sufficient for the obese population (body mass index \[BMI\] ≥30). The dose used through month 3 was closer to 0.1 mg/kg/day when total body weight was utilized. However, the use of an adjusted body weight (aBW) is common for medication dosing in obese patients. Adjusted body weight is calculated if the TBW is greater than 30% of the calculated IBW. aBW = IBW + 0.4(TBW - IBW). There is limited data available supporting the use of either IBW or aBW in dosing tacrolimus within obese patients as these patients are typically excluded from most clinical trials, particularly the pharmacokinetic trials. In addition, no literature is available comparing the two dosing weights to determine which leads to therapeutic concentrations most effectively.

Summary and Present Study Tacrolimus extended release (Astagraf) has recently been approved by the FDA as a once a day dosing regimen. This formulation has the potential to improve compliance. Current dosing recommendation for the extended release formulation in renal transplant is 0.15 mg/kg/day administered once daily in the morning. There are no specifications on appropriate dosing in obese patients or on whether to use actual, ideal or and adjusted weight. It will be advantageous to understand the pharmacokinetics of this medication in the obese to determine the appropriate dosing regimen. In this study, obese patients will be randomized to receive tacrolimus extended release 0.15 mg/kg/day based on either ideal body weight (IBW) or adjusted body weight (aBW).

Arms:
arm 1: tacrolimus extended release 0.15 mg/kg/day based on Ideal Body Weight (IBW) arm 2: tacrolimus extended release 0.15 mg/kg/day based on adjusted Body Weight (aBW)

Interventions: intervention 1: tacrolimus extended release
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
 
1
  
A pharmacokinetic analysis of tacrolimus ER dosing in obese kidney transplant 
recipients 
  
  
  
  
  
  
  
INVESTIGATOR: 
Patricia West-Thielke, PharmD, BCPS 
Director of Clinical Research 
Assistant Professor of Surgery 
Clinical Assistant Professor of Pharmacy 
office: 312-996-5695 
fax: 312-996-3579  
mobile: 312-533-1390  
pwest@uic.edu  
   
September 19, 2016 
 
SPONSOR: 
Astellas Pharma US, Inc. 
1 Astellas Way 
Northbrook, IL 60062  
Phone: 1 (800) 888-7704
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TABLE OF CONTENTS 
   
1.0       INTRODUCTION                                                                              
  
 
1.1       Background and Rationale                                                                
1.2       Description of tacrolimus extended release                    
1.3 
Chemistry, Manufacturing and Control 
Information/Pharmacology Toxicology Information 
  
2.0  
STUDY OBJECTIVE(S) 
 
 
 
 
 
 
           
  
 
2.1       Primary Objective                                                                             
  
3.0       INVESTIGATIONAL PLAN 
 
 
 
 
 
           
  
 
3.1       Study Design    
3.2       Hypothesis                                                                        
3.3       Study Population 
 
 
 
 
 
           
3.3.1.   Inclusion Criteria                                                                  
3.3.2    Exclusion Criteria    
3.3.3 Trial Population                                                       
3.4       Study Duration                                                                                  
3.5       Study Procedures 
 
 
 
 
 
          
3.5.1    Subject Screening                                                                  
3.5.2    Baseline Evaluations                                                           
3.5.3    Randomization                                                                    
3.5.4    Follow-Up Visits                                          
         
 
3.5.4.1 Scheduled Visits 
 
 
 
         
3.5.5    Termination                                                                         
3.6 
 Interim Analysis 
 
 
 
 
 
         
3.7       Adverse Events 
 
 
 
 
 
         
3.7.1    Adverse Event Reporting                                                    
3.7.2    Serious Adverse Event Reporting                                       
3.7.3    Stopping Rules  
 
 
 
 
         
3.7.4    Risk Analysis                                                                      
3.8       Data and Statistical Plan 
 
 
 
 
        
3.8.1    Data and Statistical Plan 
3.8.2    Data Collection                                                                   
 
4.0      SUMMARY OF PREVIOUS HUMAN EXPERIENCE 
 
5.0      REFERENCES                                                                                                    
 
 
6.0 
APPENDICES 
Appendix A                Table 1: Schedule of Visits & Procedures  
Appendix B                Consent to Participate in Research 
Appendix C                Case Report Forms (Eligibility, Baseline Evaluation)  
Appendix D             24 Hour PK Flowsheet 
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Appendix E                Package Insert for Tacrolimus Extended Release  
Appendix F                Investigator Curriculum Vitae and Medical License   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.0       INTRODUCTION 
1.1              Background and Rationale 
Tacrolimus exhibits significant inter- and intra-individual variability of its absorption 
and metabolism. Because of this variability, standard dosing is not an accurate 
predictor of drug exposure. In clinical use, tacrolimus whole blood trough 
concentrations are measured to ensure efficacy and safety. Furthermore, the relatively 
low bioavailability of tacrolimus is thought to be a result of the combination of poor 
water-solubility, pre-systemic metabolism of tacrolimus in the gastrointestinal tract 
and activity of the P-glycoprotein efflux pump found in the enterocytes of the GI 
tract. Tacrolimus is extensively metabolized by the cytochrome P-450 system 
(CYP3A). The plasma protein binding of tacrolimus is approximately 99%. 
Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein. The 
distribution of tacrolimus between blood and plasma depends on several factors 
including hematocrit, temperature at the time of plasma separation, drug 
concentration, and plasma protein concentration.  
 
Pharmacodynamic studies have revealed that, depending on time following 
transplantation, maintaining whole blood trough levels between 5 and 20 ng/mL 
provides adequate protection against acute rejection and limits the occurrence of 
adverse events. The management of tacrolimus blood levels is complicated by 
variable intra- and inter-patient absorption, interaction with food and concomitant 
medications, and the relatively low bioavailability of tacrolimus from the Prograf 
formulation (17 ± 10% in adult kidney transplant patients). 
 
Previous studies examining immunosuppressants have shown that drug levels in the 
immediate post-transplant period are a major determinant of subsequent acute cellular 
rejection. It is known that tacrolimus (TAC) < 10 ng/mL is associated with increased 
rates of acute cellular rejection by one month post-transplant.  
 
There is controversy regarding the appropriate dosing weight to use for 
immunosuppressants (IS). Weights use range from ideal body weight (IBW) to total 
body weight (TBW) depending on the institution and drug being dosed.  This 
becomes particularly important in the obese population when there are significant 
differences between IBW and TBW.  Our institution has always used IBW for the 
dosing of all IS due to concerns for nephrotoxicity with initial high blood levels of 
tacrolimus.  The concern in obese patients is that we are underdosing this population 
that could be at higher risk for rejection due to higher circulating concentrations of 
pro-inflammatory cytokines.  The introduction of the novel use of a robotic 
transplantation procedure at our institution for this patient population has led to 
increasing numbers of transplant in obese recipients; therefore,  we decided to re-
evaluate our dosing protocol. Data from an internal study at UIC show that our use of 
IBW for tacrolimus dosing is not sufficient for the obese population (body mass index 
[BMI] ≥30).  The dose used through month 3 was closer to 0.1 mg/kg/day when total 
body weight was utilized.  However, the use of an adjusted body weight (aBW) is 
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common for medication dosing in obese patients.  Adjusted body weight is calculated 
if the TBW is greater than 30% of the calculated IBW.  aBW = IBW + 0.4(TBW - 
IBW). There is limited data available supporting the use of either IBW or aBW in 
dosing tacrolimus within obese patients as these patients are typically excluded from 
most clinical trials, particularly the pharmacokinetic trials. In addition, no literature is 
available comparing the two dosing weights to determine which leads to therapeutic 
concentrations most effectively.  
 
Summary and Present Study 
Tacrolimus extended release (Astagraf) has recently been approved by the FDA as a 
once a day dosing regimen.  This formulation has the potential to improve 
compliance. Current dosing recommendation for the extended release formulation in 
renal transplant is 0.15 mg/kg/day administered once daily in the morning. There are 
no specifications on appropriate dosing in obese patients or on whether to use actual, 
ideal or and adjusted weight.  It will be advantageous to understand the 
pharmacokinetics of this medication in the obese to determine the appropriate dosing 
regimen. In this study, obese patients will be randomized to receive tacrolimus 
extended release 0.15 mg/kg/day based on either ideal body weight (IBW) or adjusted 
body weight (aBW).   
 
1.2       Description of tacrolimus extended release 
ASTAGRAF XL is a calcineurin-inhibitor immunosuppressant indicated for the 
prophylaxis of organ rejection in patients receiving a kidney transplant with 
mycophenolate mofetil (MMF) and corticosteroids, with or without  
basiliximab induction 
 
Risks and Medication Interaction: 
This study poses no additional risks to the patient. Tacrolimus is a mainstay of 
immunosuppressant therapy at this healthcare organization. Safety data that is 
collected during the usual standard of care visits will also be assessed in this study 
including: serum creatinine, graft function, and side effects. Additionally trough 
tacrolimus levels will be reviewed by study coordinator and dosage adjustments will 
be made as necessary to stay within goal target range. The safety data will be 
analyzed as descriptive data with reports of adverse effects in each study arm.   
 
Since tacrolimus is metabolized mainly by CYP3A enzymes, drugs or substances 
known to inhibit these enzymes may increase tacrolimus whole blood concentrations. 
Drugs known to induce CYP3A enzymes may decrease tacrolimus whole blood 
concentrations.  Dose adjustments may be needed along with frequent monitoring of 
tacrolimus whole blood trough concentrations when ASTAGRAF XL is administered 
with CYP3A inhibitors or inducers. In addition, patients should be monitored for 
adverse reactions including changes in renal function and QT prolongation. 
. 
Mycophenolic Acid Products 
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With a given dose of mycophenolic acid (MPA) products, exposure to MPA is higher 
with ASTAGRAF XL coadministration than with cyclosporine coadministration 
because cyclosporine interrupts the enterohepatic recirculation of MPA while 
tacrolimus does not. Clinicians should monitor for MPA associated adverse events 
and reduce the dose of concomitantly administered mycophenolic acid products, if 
needed. 
 
Grapefruit Juice 
Grapefruit juice inhibits CYP3A-enzymes resulting in increased tacrolimus whole 
blood trough concentrations, and patients should avoid eating grapefruit or drinking 
grapefruit juice in combination with ASTAGRAF XL. 
 
Alcohol 
Consumption of alcohol with ASTAGRAF XL may increase the rate of release of 
tacrolimus and/or adversely alter the pharmacokinetic properties and the effectiveness 
and safety of ASTAGRAF XL. Therefore, alcoholic beverages should not be 
consumed with ASTAGRAF XL. 
 
Protease Inhibitors 
Most protease inhibitors inhibit CYP3A enzymes and may increase tacrolimus whole 
blood concentrations. It is recommended to avoid concomitant use of tacrolimus with 
nelfinavir unless the benefits outweigh the risks. Whole blood concentrations of 
tacrolimus are markedly increased when coadministered with telaprevir or with 
boceprevir. Monitoring of tacrolimus whole blood concentrations and tacrolimus-
associated adverse reactions, and appropriate adjustments in the dosing regimen of 
tacrolimus are recommended when tacrolimus and protease inhibitors (e.g., ritonavir, 
telaprevir, boceprevir) are used concomitantly. 
 
Antifungal Agents 
Frequent monitoring of whole blood concentrations and appropriate dosage 
adjustments of tacrolimus are recommended when concomitant use of the following 
antifungal drugs with tacrolimus is initiated or discontinued. Azoles: Voriconazole, 
posaconazole, itraconazole, ketoconazole, fluconazole and clotrimazole inhibit 
CYP3A metabolism of tacrolimus and increase tacrolimus whole blood 
concentrations. When initiating therapy with voriconazole or posaconazole in patients 
already receiving tacrolimus, it is recommended that the tacrolimus dose be initially 
reduced to one-third of the original dose and the subsequent tacrolimus doses be 
adjusted based on the tacrolimus whole blood concentrations. Caspofungin is an 
inducer of CYP3A and decreases whole blood concentrations of tacrolimus. 
 
Calcium Channel Blockers 
Verapamil, diltiazem, nifedipine, and nicardipine inhibit CYP3A metabolism of 
tacrolimus and may increase tacrolimus whole blood concentrations. Monitoring of 
whole blood concentrations and appropriate dosage adjustments of tacrolimus are 
recommended when these calcium channel blocking drugs and tacrolimus are used 
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concomitantly. 
 
Antibacterials 
Erythromycin, clarithromycin, troleandomycin and chloramphenicol inhibit CYP3A 
metabolism of tacrolimus and may increase tacrolimus whole blood concentrations. 
Monitoring of blood concentrations and appropriate dosage adjustments of tacrolimus 
are recommended when these drugs and tacrolimus are used concomitantly. 
 
Antimycobacterials 
Rifampin and rifabutin are inducers of CYP3A enzymes and may decrease 
tacrolimus whole blood concentrations. Monitoring of whole blood concentrations 
and appropriate dosage adjustments of tacrolimus are recommended when these 
antimycobacterial drugs and tacrolimus are used concomitantly. 
 
Anticonvulsants 
Phenytoin, carbamazepine and phenobarbital induce CYP3A enzymes and may 
decrease tacrolimus whole blood concentrations. Monitoring of whole blood 
concentrations and appropriate dosage adjustments of tacrolimus are recommended 
when these drugs and tacrolimus are used concomitantly. Concomitant administration 
of phenytoin with tacrolimus may also increase phenytoin plasma concentrations. 
Thus, frequent monitoring of phenytoin plasma concentrations and adjusting the 
phenytoin dose as needed are recommended when tacrolimus and phenytoin are 
administered concomitantly. 
 
St. John’s Wort (Hypericum perforatum) 
St. John’s Wort induces CYP3A enzymes and may decrease tacrolimus whole blood 
concentrations. Monitoring of whole blood concentrations and appropriate dosage 
adjustments of tacrolimus are recommended when St. John’s Wort and tacrolimus are 
coadministered. 
 
Gastric Acid Suppressors/Neutralizers 
Lansoprazole and omeprazole, the proton pump inhibitors (PPIs), as CYP2C19 and 
CYP3A4 substrates, share the same CYP3A4 system with tacrolimus for their hepatic 
elimination, and may potentially competitively inhibit the CYP3A4 metabolism of 
tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, 
especially in transplant patients who are intermediate or poor CYP2C19 metabolizers 
in which the PPIs metabolic pathway shifts from 2C19 to 3A4, as compared to those 
patients who are efficient CYP2C19 metabolizers. Cimetidine, a CYP2C19 and 
CYP3A4 inhibitor, may also inhibit the CYP3A4 metabolism of tacrolimus and 
thereby substantially increase tacrolimus whole blood concentrations. 
Coadministration with magnesium and aluminum hydroxide antacids increase 
tacrolimus whole blood concentrations. Monitoring of whole blood concentrations 
and appropriate dosage adjustments of tacrolimus are recommended when these drugs 
and tacrolimus are used concomitantly. 
 
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Other Drugs 
Amiodarone, bromocriptine, nefazodone, metoclopramide, danazol, ethinyl estradiol 
and methylprednisolone may inhibit CYP3A metabolism of tacrolimus and increase 
tacrolimus whole blood concentrations. Monitoring of blood concentrations and 
appropriate dosage adjustments of tacrolimus are recommended when these drugs and 
tacrolimus are coadministered. 
 
Dosage and Administration 
The initial dose of tacrolimus extended release will be tacrolimus extended release  
0.15 mg/kg/day given in the morning based on either IBW or aBW depending on 
which arm the patient is randomized.  Subsequent doses will be adjusted to maintain 
the target whole blood trough level of 8-12 ng/mL per institution transplant protocols. 
 
ASTAGRAF XL is a once daily extended-release oral formulation of tacrolimus. 
To ensure consistent and maximum possible drug exposure, ASTAGRAF XL 
capsules should be taken consistently every morning, preferably on an empty stomach 
at least 1 hour before a meal or at least 2 hours after a meal.  ASTAGRAF XL should 
be swallowed whole and should not be chewed, divided, or crushed.  Patients should 
not eat grapefruit or drink grapefruit juice in combination with ASTAGRAF XL.  If a 
dose of ASTAGRAF XL is missed, the dose may be taken up to 14 hours after the 
scheduled time.  Beyond the 14-hour time frame, the patient should wait until the 
usual scheduled time the following morning to take the next regular daily dose. It is 
not recommended to double the dose of ASTAGRAF XL to make up for the missed 
dose. 
 
Supply and Storage 
ASTAGRAF XL is supplied in short, square bottles as well as in blister cartons; the 
statement 'ONCE DAILY' appears on its label.  ASTAGRAF XL and tacrolimus 
immediate-release capsules are further differentiated by different color schemes. 
 
Store and Dispense 
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). 
 
1.3 Chemistry, Manufacturing and Control Information/Pharmacology 
Toxicology Information 
We believe our application may rely on the previous FDA’s acceptance of the CMC 
and Pharmacology and Toxicology information related to the approved marketed drug 
intended for this investigation. 
 
2.0        STUDY OBJECTIVES 
2.1        Primary Objective 
The primary objective of this research is to determine the best dosing method of 
tacrolimus extended release for obese kidney transplant recipients. 
 
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3.0       INVESTIGATIONAL PLAN 
3.1       Study Design  
This is a prospective, randomized, single-center, dual arm study to be conducted 
under an FDA exempt protocol.  Our site will enroll 25 eligible patients for this study. 
Subjects will be followed for 14 days (+/- 3 days).  We anticipate that it will take one 
year to enroll 25 patients. 
 
3.2       Hypothesis  
Obese patients will require a tacrolimus extended release dose that is greater than that 
calculated using ideal body weight.    
 
3.3       Study Population 
3.3.1    Inclusion Criteria 
1. The subject is a recipient of a living donor or deceased donor kidney only 
transplant  
2. Subject is > 18 years of age 
3. BMI≥30 on POD 0 
 
3.3.2    Exclusion Criteria 
1. Multi-organ transplant 
2. Subjects taking tacrolimus pre-transplant (i.e. positive crossmatch transplants 
or re-transplants) 
3. Patients undergoing simultaneous sleeve gastrectomy at the time of transplant.  
 
3.3.3 Trial Population 
This study will randomize de novo kidney transplant recipients who are at least 18 
years of age and obese as evidenced by a BMI ≥ 30 on the day of transplantation 
POD 0.  Demographics at this institution are approximately 50% African American, 
35% Hispanic, and 15% Caucasian.   
 
3.4       Study Duration 
Subjects will be followed for a period of 14 days.  We anticipate that it will take one 
year to enroll 25 patients. 
 
3.5       Study Procedures  
3.5.1    Subject Screening 
Subjects will be recruited from patients undergoing kidney transplantation at the 
University of Illinois Health System.  Medical history and pre-operative surgical visit 
and laboratory results will be utilized for the subject screening.   
 
 3.5.2      Baseline Evaluations 
• Demographics: age, gender, and race 
• Height, weight and BMI  
• Blood pressure 
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• Results of Standard of Care Preoperative CBC  
• Medical History, Physical and Laboratory Tests  
• Results of Standard of Care Preoperative Urine pregnancy test (for female 
subjects) 
 
3.5.3        Randomization  
Patients will be randomized to receive tacrolimus extended release 0.15 mg/kg/day 
based on either IBW or aBW within 48 hours of transplant.   
 
3.5.4     Follow-Up Care 
3.5.4.1  Scheduled Follow Up 
Post-transplantation, three pharmacokinetic (PK) assessments will be performed over 
a 14-day period in order to determine area under the curve (AUC).  
 
On Study Day 1, the first PK assessment will be done on the day the patient receives 
the first dose of study drug. This may be on post-operative day (POD) 0-2 depending 
on post-operative urine output and attending surgeon preference.   
 
Additional trough level measurements will be obtained pre-dose on days 2-5.  
 
Study Day 7 will be defined as the second PK assessment and must occur between 
POD 5 – 9 and prior to discharge. 
 
Study Day 14 will be defined as the third PK assessment and must occur between 6 – 
8 days after the second PK assessment which correlates to POD 11-17. 
 
Pharmacokinetic Assessments: 
Study Day 1, 7, and 14 PK blood sampling points include: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 
12 and 24 hours after the dose of tacrolimus extended release. This results in a total of 
33 blood samples. 
 
3.5.5        Termination 
If a subject decides to withdraw from the study and desires the sole use of standard of 
care immunosuppressant dosing, the subject will be withdrawn and standard of care 
immunosuppressant dosing will be utilized.   
 
3.6              Interim Analysis 
No interim analysis are planned. 
 
3.7           Adverse Events 
3.7.1        Adverse Event Reporting 
Any adverse event will be reported to the University of Illinois at Chicago 
Institutional Review Board (IRB) within 15 business days by submitting a prompt 
report.  The Chairman of the IRB will be notified via this mechanism.   
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(1)        Subject's initials and subject number 
(2)        Investigator's name 
(3)        Protocol title and number 
(4)        Subject's date of birth, gender, and race 
(5)        Concomitant medication(s): dose, route, duration of treatment, date of last  
dose 
(6)        Information regarding the adverse event: 
 
(i)         description 
 
(ii)        date(s) the event began and ended 
 
(iii)       whether the experience resulted in death or was life-threatening 
 
(iv)       whether hospitalization was required or prolonged 
 
(v)        any treatment(s) required 
 
(vi)       outcome(s) of treatment(s) 
 
(vii)      Investigator's determination of relationship to the test article(s). 
 
All adverse events will be recorded on appropriate case report form(s). A summary of 
the adverse events including frequency, type, and severity will be reported. 
 
3.7.2        Serious Adverse Event Reporting 
Any adverse event will be reported to the University of Illinois at Chicago 
Institutional Review Board (IRB) within 5 business days by submitting a prompt 
report.  The Chairman of the IRB will be notified via this mechanism.   
 
(1)        Subject's initials and subject number 
(2)        Investigator's name 
(3)        Protocol title and number 
(4)        Subject's date of birth, gender, and race 
(5)        Concomitant medication(s): dose, route, duration of treatment, date of last 
dose 
(6)        Information regarding the adverse event: 
 
(i)         description 
 
(ii)        date(s) the event began and ended 
 
(iii)       whether the experience resulted in death or was life-threatening 
 
(iv)       whether hospitalization was required or prolonged 
 
(v)        any treatment(s) required 
 
(vi)       outcome(s) of treatment(s) 
 
(vii)      Investigator's determination of relationship to the test article(s). 
 
All adverse events will be recorded on appropriate case report form(s). A summary of 
the adverse events including frequency, type, and severity will be reported. 
 
3.7.3        Stopping Rules 
The investigators will stop the study in the event that the following events occur.    
 
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(1)  One subject experiences death related to tacrolimus extended release.   
 
 
In the event of study termination, the investigator will notify the FDA and IRB that 
enrollment is stopped. 
 
3.7.4        Risk Analysis  
The study drug poses no additional risks to the patient. Tacrolimus is a mainstay of 
immunosuppressant therapy at this healthcare organization. Risks from the study 
procedures include loss of confidentiality and slight pain, bruising or infection from 
the blood draws. Safety data that is collected during the usual standard of care visits 
will also be assessed in this study including: serum creatinine, graft function, and side 
effects. Additionally trough tacrolimus levels will be reviewed by study coordinator 
and dosage adjustments will be made as necessary to stay within goal target range. 
The safety data will be analyzed as descriptive data with reports of adverse effects in 
each study arm.  
 
3.8            Data and Statistical Analysis 
3.8.1    Data and Statistical Plan 
All demographic data, pharmacokinetic parameters, and laboratory data will be 
summarized using descriptive statistics. For continuous data, the mean, standard 
deviation, median, minimum and maximum will be reported and compared using a 
paired t-test. For categorical data, percent and frequency will be reported. For the 
endpoint comparing percents between aBW and IBW, Chi-square analyses with 
Fisher’s Exact as needed will be conducted.  Noncompartmental pharmacokinetic 
parameters (AUC0-24, Cmax, Tmax, C24, T½) will be calculated from blood 
concentration-time data. In addition, pharmacokinetic profiles will be analyzed using 
nonlinear mixed effects modeling to assess differences in rate of absorption and 
clearance between the aBW and IBW groups.  A sample size of 10 subjects per group 
will be recruited for this pilot PK investigation. 
 
3.8.2    Data Collection and Storage  
We will collect relevant medical history information from the subject's medical 
records including illnesses and hospitalizations that occurred prior to or occur after 
subject participation in the research.  Additionally, we will collect age, gender, race, 
height, weight, BMI, CBC, medical history, physical examination, laboratory tests, 
and urine pregnancy test (for female subjects). All data will be recorded on case 
report forms and used for analysis.  Results will be compiled to assess aggregate 
outcomes and address the issues of reliability and efficacy.  Data will be maintained 
in a database in a password protected computer. 
 
3.8.3 Pharmacogenetic Analysis 
One additional sample will be stored for potential future analysis.   
 
3.8.4 Endpoints 
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1.  Difference in tacrolimus exposure (AUC24) in obese patients dosed using 
aBW compared to IBW.  
2. Difference in the time to a therapeutic tacrolimus trough level in the aBW 
group compared to the IBW group. 
 
While there is limited data for dosing tacrolimus in the obese patient population 
internal data conducted at the University of Illinois Health System has demonstrated a 
statistically significant difference between dosing based on ideal body weight and 
actual body weight. Additionally the acute rejection rate was 55% in obese patients 
and 22% in non-obese patients, possibly as a result of under dosing in the obese 
population. It is well established that low tacrolimus levels especially in the first week 
of transplant are associated with acute rejections. At the same time high tacrolimus 
levels increase the risk of nephrotoxicity.  Therefore, it is vital that the correct weight 
be utilized in dosing tacrolimus extended release, especially in a medication that will 
require a full day to wait for a dosage adjustment. The proposed endpoints will give 
the transplant community a better understanding of which weight to utilize in dosing 
this unique patient population. The AUC calculation will help to optimize the 
appropriate dosing in the obese patients to ensure a therapeutic level is maintained in 
a medication with high lipophilicity.  
 
4.0 SUMMARY OF PREVIOUS HUMAN EXPERIENCE 
We believe our application can rely on the FDA’s acceptance of the previous human 
experience related to the approved marketed drug intended for investigation.  Please 
refer to pages 27-30 of the package insert.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.0 REFERENCES 
Kino, T., et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. 
Immunosuppressive effect of FK-506 in vitro. J. Antibiot. 40, 1256-1265 (1987). 
 
Laskow, D.A., et al. The role of tacrolimus in adult kidney transplantation: a review. 
Clin. Transplant. 12, 489-503 (1998). 
 
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442 (2009). 
 
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transplant are associated with reduced rates of acute rejection. Clin. Transplant. 23, 
462-468 (2009). 
 
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immunosuppressive drugs: new insight and preventive strategies. Current opinion in 
critical care 7, 384-389 (2001). 
 
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15
Appendix A                  
Table 1: Schedule of Visits & Procedures  
A pharmacokinetic analysis of tacrolimus ER dosing in obese kidney transplant 
recipients 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of Visits and Procedures 
Prior to 
Transplant  
Visit 1 
Visit 2 
Visit 3 
Post Operative Day 
 
0-2 
5-9 
11-17 
Informed Consent 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
Randomization 
X 
 
 
 
Medical History 
X 
 
 
 
Physical  Exam 
X 
 
 
 
Demographics  
X 
 
 
 
Height 
X 
 
 
 
Weight/BMI 
X 
 
 
 
Basic chemistry profile 
X 
X 
X 
X 
Hematology profile 
X 
X 
X 
X 
Urine pregnancy test (if female, as needed) 
X 
 
 
 
Tacrolimus level (0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 
hours post dose) 
 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
Adverse Event Reporting  
X 
X 
X 
X 
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16
Appendix B                Consent to Participate in Research 
Appendix C                Case Report Forms (Eligibility, Baseline Evaluation) 
Appendix D   
24 Hour PK Flowsheet 
Appendix E                Package Insert for Tacrolimus Extended Release  
Appendix F                Investigator Curriculum Vitae and Medical License   
  
  
  
  
 
 
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