Comparative Bioavailability of Myfenax® and CellCept® in Kidney Transplant Patients

Study Overview
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Brief Summary
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The purpose of the study is to further investigate how much of the drug substance mycophenolate mofetil can be found in the blood of patients with kidney or renal transplants when treated with Myfenax® or CellCept®. Additionally, the safety and side effects of the two products will be compared. All information already available on these products indicates that the safety profiles of the two products will be the same.

Official Title
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Comparative Bioavailability of Myfenax® (Teva) and CellCept® (Roche) in Stable Patients After Renal Transplantation

Conditions
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Stable Renal Transplant Recipients

Intervention / Treatment
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* Drug: mycophenolate mofetil (Myfenax)
* Drug: mycophenolate mofetil (Cellcept)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Renal transplant recipients at least 12 months post-transplantation aged ≥ 18 years. Maintenance treatment with mycophenolate mofetil (in combination with tacrolimus with or without corticosteroids). Stable dose of mycophenolate mofetil (≥ 500 mg twice daily) with no changes in immunosuppressive regimen for at least 6 weeks prior to the start of the study. Stable renal graft function for at least 3 months. Female patients must be either post-menopausal for ≥ 1 year, be surgically sterilized or a negative pregnancy test will be required immediately prior to study entry and such patients must continue to use effective contraception. Willingness to undergo the study-related procedures. Ability to comprehend and willingness to sign informed consent form. Exclusion Criteria: History of allergy to mycophenolate mofetil, mycophenolic acid or any of the ingredients. Multi-organ recipients (e.g., kidney and pancreas) or previous transplant with any organ other than kidney. Rejection within the past 6 months prior to the start of the study. Severe clinically relevant co-existing disease. History of cancer other than skin cancer that has been cured. History of serious clinically relevant digestive system disease during the last 12 months prior to start of the study. Known or suspected hereditary deficiency of hypoxanthine-guanine-phosphoribosyltransferase (e.g., Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome). Known or suspected liver impairment. Clinically significant thrombocytopenia, anaemia, leukopenia, or neutropenia Clinically significant laboratory and/or physical changes during the last 2 months prior to the start of the study. Use of azathioprine, cholestyramine, sevelamer, or probenecid within 2 weeks prior to the first administration of study medication. Change in concomitant medication during the 6 weeks prior to start of the study. Use of any drug, prescribed or over-the-counter, (except stable concomitant medication) within 2 weeks prior to the first administration of study medication. Planned or expected requirement for the use of live attenuated vaccines during the study. Positive testing for HIV, Hepatitis B and C. Clinical symptoms or laboratory evidence of cytomegalovirus infection in the last 6 month. Pregnant or breast-feeding women. Women of childbearing potential unable or unwilling to practice effective contraceptive measures for the duration of the study and for 6 weeks after the end of the study. History of known or suspected alcohol or drug abuse. Any other condition of the patient that, in the opinion of the investigator may compromise evaluation of the study treatment or may jeopardize patient's compliance or adherence to protocol requirements. Previous enrollment in this study or participation in any other drug investigational trial within the past 6 weeks prior to enrollment.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reference/Test/Test<br>The reference product was CellCept® and test product was Myfenax®. In period I, participants received CellCept on Days 1-14. In period II, participants crossed-over to receive Myfenax on Days 15-28. In period III, participants received Myfenax until the end of the study (Days 29-112). Doses of mycophenolate mofetil were at least 500 mg twice daily, morning and evening. | Drug: mycophenolate mofetil (Myfenax)<br>* Each participant received at least 500 mg orally, twice daily (morning and evening) during those study periods labeled as 'T' (test drug). Participants receive the dose equivalent to the pre-study dose (within the recommended therapeutic range) of mycophenolate mofetil.<br>* Other names: Myfenax®;Drug: mycophenolate mofetil (Cellcept)<br>* Each participant received at least 500 mg orally, twice daily (morning and evening) during those study periods labeled as 'R' (reference drug). Participants receive the dose equivalent to the pre-study dose (within the recommended therapeutic range) of mycophenolate mofetil.<br>* Other names: CellCept®;|
| Experimental: Test/Reference/Reference<br>The test product was Myfenax® and the reference product was CellCept®. In period I, participants received Myfenax on Days 1-14. In period II, participants crossed-over to receive CellCept on Days 15-28. In period III, participants received CellCept until the end of the study (Days 29-112). Doses of mycophenolate mofetil were at least 500 mg twice daily, morning and evening. | Drug: mycophenolate mofetil (Myfenax)<br>* Each participant received at least 500 mg orally, twice daily (morning and evening) during those study periods labeled as 'T' (test drug). Participants receive the dose equivalent to the pre-study dose (within the recommended therapeutic range) of mycophenolate mofetil.<br>* Other names: Myfenax®;Drug: mycophenolate mofetil (Cellcept)<br>* Each participant received at least 500 mg orally, twice daily (morning and evening) during those study periods labeled as 'R' (reference drug). Participants receive the dose equivalent to the pre-study dose (within the recommended therapeutic range) of mycophenolate mofetil.<br>* Other names: CellCept®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Curve (AUC(0-6h)) of Mycophenolate Mofetil | Area under the plasma concentration-time curve during a dosage interval at steady state (calculated using the trapezoidal rule, from t = 0 to t = 6 hours). | Day 14 and Day 28 (end of first two cross-over periods) before drug administration and at 30 min, 1 hour, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after drug administration | 
| Area Under the Plasma Concentration-time Curve (AUC(0-tau)) of Mycophenolate Mofetil | For participants with a 0-12h profile: Area under the plasma concentration-time curve during a dosage interval at steady state (calculated using the trapezoidal rule, from t = 0 to t = 12 hours). For participants with a 0-6h profile: AUC(0-tau) was calculated based on AUC(0-6h) using the extrapolation formula according to Fleming. | Day 14 and Day 28 (end of first two cross-over periods) before drug administration and at 30 min, 1 hour, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after drug administration | 
| Maximum Observed Plasma Concentration (Cmax) of Mycophenolate Mofetil | Cmax was directly obtained from measured values of plasma concentrations. | Day 14 and Day 28 (end of first two cross-over periods) before drug administration and at 30 min, 1 hour, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Minimum Observed Plasma Concentration (Cmin) of Mycophenolate Mofetil | Cmin was directly obtained from measured values of plasma concentrations. | Day 14 and Day 28 (end of first two cross-over periods) before drug administration and at 30 min, 1 hour, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after drug administration | 
| Plasma Concentrations of Mycophenolate Mofetil in Pre-Administration Samples (Cpd) | Cpd was directly obtained from measured values of plasma concentrations. | Day 14 and Day 28 (end of first two cross-over periods) before drug administration | 
| Degree of Fluctuation of the Concentration Levels of Mycophenolate Mofetil Over One Dosing Interval (PTF) | PTF was calculated as: (Cmax-Cmin)/(AUCt/t)*100 | Day 14 and Day 28 (end of first two cross-over periods) before drug administration | 
| Time Corresponding to Occurrence of Cmax (Tmax) of Mycophenolate Mofetil | Tmax was directly obtained from measured values. | Day 14 and Day 28 (end of first two cross-over periods) before drug administration | 
| Summary of Participants With Adverse Events | Summary of adverse events across three study time periods. The on-treatment time frame spanned the time during which study drug was administered. Relation to study drug was assessed by the investigator. The Adverse Event count includes serious and non-serious AEs. A serious AE (SAE) was any event that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or congenital anomaly/birth defect or was an important medical event could have jeopardized the patient's safety or required medical or surgical intervention to prevent one of the outcomes listed above. Severity was measured on a three-point scale: mild, moderate, severe. | Day 1 up to Day 112 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal transplantation, mycophenolate mofetil, pharmacokinetics, immunosuppression