A Study of the Correlation Between Pharmacokinetic and Pharmacodynamic Parameters of CellCept (Mycophenolate Mofetil).

Study Overview
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Brief Summary
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This study will evaluate the correlation between the pharmacokinetic and pharmacodynamic parameters of CellCept in patients undergoing primary kidney transplantation, in order to assess the impact on clinical outcome and the risks of acute rejection. All patients will receive oral CellCept, 1g twice daily, and pharmacokinetic and pharmacodynamic parameters will be measured at weeks 2, 4, 12 and 24. The anticipated time on study treatment is 24 weeks.

Official Title
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Relationships Between Pharmacokinetic and Pharmacodynamic Strategies for Assessment of the Risks for Acute Rejection and Side Effects of Mycophenolate Mofetil

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Drug: mycophenolate mofetil
* Drug: antibody induction
* Drug: Cyclosporine
* Drug: corticosteroid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, 18 to 65 years of age Patients undergoing primary kidney transplantation Exclusion Criteria: Recipients of multiple organ transplants Prior therapy with CellCept Presence or history of malignancies, except for successfully treated basal or squamous cell carcinoma of the skin Active peptic ulcer or active serious digestive system disease that may affect the absorption of CellCept

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mycophenolate Mofetil Monotherapy<br>Participants received an initial dose of mycophenolate mofetil (MMF), 1 gram (g), orally (PO), twice per day (BID), within 5 days of transplant for 24 weeks. Participants also received concurrent antibody induction, cyclosporine, and corticosteroids as needed according to center's practice. | Drug: mycophenolate mofetil<br>* 1 g PO BID for 24 weeks<br>* Other names: CellCept;Drug: antibody induction<br>* According to manufacturer recommendation<br>Drug: Cyclosporine<br>* According to manufacturer recommendation<br>Drug: corticosteroid<br>* According to manufacturer recommendation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Acute Rejection | Diagnosis of acute rejection was suspected in any participant with an increase in serum creatinine greater than or equal to (≥) 25 percent (%). All suspected acute rejections were confirmed by biopsy. The start date of acute rejection was identified as the date of biopsy. | Day 1, Weeks 2, 4, 12, 24, and 28 | 
| Time to Rejection | The mean time, in days, from the date of enrollment to date of biopsy confirming acute rejection. | Day 1, Weeks 2, 4, 12, 24, and 28 | 
| Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR) | BPAR was defined according to 1997 Banff Criteria as a biopsy Banff grade of IA, IB, IIA, IIB, or III. Grade IA was defined as significant interstitial infiltration with greater than (>)25% of parenchyma affected, and foci of moderate tubulitis with >4 mononuclear cells per tubular cross section or group of 10 tubular cells. Grade IB was defined as significant interstitial infiltration with >25% parenchyma affected, and foci of severe tubulitis with >10% mononuclear cells per tubular cross section or group of 10 tubular cells. Grade IIA was defined as mild to moderate intimal arteritis. Grade IIB was defined as severe intimal arteritis comprising >25% of the luminal area. Grade III was defined as transmural arteritis and/or arterial fibrinoid changes and necrosis of medial smooth muscle cells. | Day 1, Weeks 2, 4, 12, 24, and 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Graft Loss | An allograft was presumed to be lost if a participant started dialysis and was not able to subsequently be removed from dialysis. | Day 1, Weeks 2, 4, 12, 24, and 28 | 
| Percentage of Participants Surviving |  | Day 1, Weeks 2, 4, 12, 24, and 28 | 
| Total Mycophenolate Acid (MPA) by Visit and Timepoint | Drug quantification of total MPA (micrograms per milliliter [mcg/mL]) in the plasma was measured at time (T) = 0 minutes (min), 40 mins, and 120 mins. | Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up Visit), and any unscheduled visits | 
| Free MPA (mcg/mL) by Visit | Drug quantification of free MPA in the plasma was measured at T = 0, 40, and 120 mins. | Weeks 2, 4, 12, 24, safety follow-up (Week 28), and any unscheduled visits | 
| MPA Area Under the Concentration - Time Curve From Time 0 to 12 Hours (AUC0-12) (mcg/mL) by Visit | The AUC0-12 of MPA was estimated on the validated limited sampling strategy, AUC (milligrams multiplied by height over liter [mg.h/L]) = 7.182 + 4.607 multiplied by (*) concentration at 0 minutes (C0)+ 0.998 * the concentration at 40 minutes (C0.67) + 2.149 * the concentration at 120 minutes (C2). | Predose and 40 minutes and 2 hours postdose at Weeks 2, 4, 12, and 24, and at the Safety follow-up (Week 28) | 
| Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | IMPDH activity in peripheral blood mononuclear cells (PBMCs) was measured at 2 timepoints per visit, 0 and 120 minutes and presented in enzyme units. The unit of measure of enzyme activity is U. One U is defined as the amount of the enzyme that produces a certain amount of enzymatic activity that is, the amount that catalyzes the conversion of 1 micro mole of substrate per minute under pre-specified conditions (temperature, pH). | BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits | 
| IMPDH Expression I by Visit and Timepoint | IMPDH I gene expression was measured by real time polymerase chain reaction (QRT-PCR) based cytokine measurement of PBMCs at 2 timepoints per visit, 0 and 120 minutes and expressed as number of messenger ribonucleic acid (mRNA) copies per cell (copies/cell). | BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits | 
| IMPDH Expression II by Visit and Timepoint | IMPDH II gene expression was measured by QRT-PCR based cytokine measurement of PBMCs at 2 timepoints per visit, 0 and 120 minutes and expressed as number of mRNA copies/cell. | BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits | 
| Interleukin 8 (IL-8) Expression by Visit and Timepoint | IL-8 gene expression was measured by QRT-PCR based cytokine measurement of PBMCs at 2 timepoints per visit, 0 and 120 minutes and expressed as number of mRNA copies/cell. | BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits | 
| Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | TNF gene expression was measured by QRT-PCR based cytokine measurement of PBMCs at 2 timepoints per visit, 0 and 120 minutes and expressed as number of mRNA copies/cell. | BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits | 
| Percentage of Participants With Infection | Infections were graded according to the World Health Organization (WHO) worst grade observed. | BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up) | 
| Percentage of Participants With Gastrointestinal Toxicities | Gastrointestinal adverse events (AEs) according to WHO worst grade observed. | BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-up Visit) | 
| Percentage of Participants With Hematologic Toxicity | Hematological toxicities graded according to WHO worst grade observed (Grade 1=mild, Grade 2=moderate). | BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up) | 
| Spearman's Rank Correlation Coefficient Between MPA Levels and IMPDH Activity | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. | BL and Weeks 2, 4, 12, and 24 | 
| Spearman's Rank Correlation Coefficient Between IMPDH I Expression and MPA Levels | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. | BL and Weeks 2, 4, 12, and 24 | 
| Spearman's Rank Correlation Coefficient Between IMPDH I Expression and Free Fraction | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. | BL and Weeks 2, 4, 12, and 24 | 
| Spearman's Rank Correlation Coefficient Between IMPDH II Expression and MPA Levels | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. | BL and Weeks 2, 4, 12, and 24 | 
| Spearman's Rank Correlation Coefficient Between IMPDH II Expression and Free Fraction | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. | BL and Weeks 2, 4, 12, and 24 | 
| Spearman's Rank Correlation Coefficient Between IMPDH Inhibition and Risk of Acute Rejection | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. | BL and Weeks 2, 4, 12, and 24 | 
| Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Infection | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. | BL and Weeks 2, 4, 12, and 24 | 
| Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Hematologic Toxicity | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. | BL and Weeks 2, 4, 12, and 24 | 
| Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Gastrointestinal Toxicity | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. | BL and Weeks 2, 4, 12, and 24 | 
| Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Infection | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. | BL and Weeks 2, 4, 12, and 24 | 
| Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Hematologic Toxicity | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. | BL and Weeks 2, 4, 12, and 24 | 
| Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Gastrointestinal Toxicity | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. | BL and Weeks 2, 4, 12, and 24 |