Stable Renal Transplant Recipients
Conditions
Keywords
renal transplantation, mycophenolate mofetil, pharmacokinetics, immunosuppression
Brief summary
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.
Interventions
DRUGmycophenolate mofetil (Myfenax)
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.
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.
Sponsors
Parexel
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve (AUC(0-6h)) of Mycophenolate Mofetil | 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 during a dosage interval at steady state (calculated using the trapezoidal rule, from t = 0 to t = 6 hours). |
| Area Under the Plasma Concentration-time Curve (AUC(0-tau)) of Mycophenolate Mofetil | 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 | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Mycophenolate Mofetil | 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 | Cmax was directly obtained from measured values of plasma concentrations. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time Corresponding to Occurrence of Cmax (Tmax) of Mycophenolate Mofetil | Day 14 and Day 28 (end of first two cross-over periods) before drug administration | Tmax was directly obtained from measured values. |
| Minimum Observed Plasma Concentration (Cmin) of Mycophenolate Mofetil | 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 | Cmin was directly obtained from measured values of plasma concentrations. |
| Summary of Participants With Adverse Events | Day 1 up to Day 112 | 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. |
| Plasma Concentrations of Mycophenolate Mofetil in Pre-Administration Samples (Cpd) | Day 14 and Day 28 (end of first two cross-over periods) before drug administration | Cpd was directly obtained from measured values of plasma concentrations. |
| Degree of Fluctuation of the Concentration Levels of Mycophenolate Mofetil Over One Dosing Interval (PTF) | Day 14 and Day 28 (end of first two cross-over periods) before drug administration | PTF was calculated as: (Cmax-Cmin)/(AUCt/t)\*100 |
Participant flow
Pre-assignment details
A total of 100 subjects were planned. A total of 47 subjects were screened in the study. Four subjects were not randomised, i.e., two subjects withdrew consent, one subject had a protocol violation, and one subject was a screening failure (did not meet eligibility criteria).
Participants by arm
| Arm | Count |
|---|---|
| Reference/Test/Test 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. | 22 |
| Test/Reference/Reference 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. | 21 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period I (Days 1-14) | Adverse Event | 1 | 0 |
| Period III (Days 29-112) | Adverse Event | 1 | 1 |
Baseline characteristics
| Characteristic | Reference/Test/Test | Test/Reference/Reference | Total |
|---|---|---|---|
| Age, Continuous | 49.7 years STANDARD_DEVIATION 13.73 | 51.7 years STANDARD_DEVIATION 13.55 | 50.7 years STANDARD_DEVIATION 13.52 |
| Body Mass Index | 26.24 kg/m^2 STANDARD_DEVIATION 3.756 | 25.93 kg/m^2 STANDARD_DEVIATION 3.422 | 26.09 kg/m^2 STANDARD_DEVIATION 3.557 |
| Height | 1.711 meters STANDARD_DEVIATION 0.1061 | 1.718 meters STANDARD_DEVIATION 0.0983 | 1.714 meters STANDARD_DEVIATION 0.1012 |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 21 participants | 21 participants | 42 participants |
| Sex: Female, Male Female | 11 Participants | 8 Participants | 19 Participants |
| Sex: Female, Male Male | 11 Participants | 13 Participants | 24 Participants |
| Weight | 77.19 kilograms STANDARD_DEVIATION 14.856 | 77.23 kilograms STANDARD_DEVIATION 15.661 | 77.21 kilograms STANDARD_DEVIATION 15.072 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 15 / 43 | 16 / 42 | 26 / 43 |
| serious Total, serious adverse events | 1 / 43 | 1 / 42 | 1 / 43 |
Outcome results
Primary
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).
Time frame: 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
Population: PK population. Two participants were excluded from the PK population: one dropped out of the study during the first period so had no PK samples. The other was omitted due to protocol violations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CellCept | Area Under the Plasma Concentration-time Curve (AUC(0-6h)) of Mycophenolate Mofetil | 33.523 hour* µg /ml | Standard Deviation 15.1265 |
| Myfenax | Area Under the Plasma Concentration-time Curve (AUC(0-6h)) of Mycophenolate Mofetil | 31.100 hour* µg /ml | Standard Deviation 15.4198 |
Comparison: A total of 100 subjects were planned to be enrolled, allowing for 10% drop-out rate. Based on previous single dose studies, the intra-subject coefficients of variation were 14% and 50% for AUC and Cmax, respectively. Based on the literature similar intra subject coefficients of variation were observed in steady-state patients. With these expected CV(%) and an expected ratio of Cmax within 0.95 and 1.05, the study should have a power of at least 80 % to show bioequivalence with 80 subjects.90% CI: [0.865, 0.984]ANOVA
Primary
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.
Time frame: 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
Population: PK population. Two participants were excluded from the PK population: one dropped out of the study during the first period so had no PK samples. The other was omitted due to protocol violations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CellCept | Area Under the Plasma Concentration-time Curve (AUC(0-tau)) of Mycophenolate Mofetil | 49.846 hour* µg /ml | Standard Deviation 20.8278 |
| Myfenax | Area Under the Plasma Concentration-time Curve (AUC(0-tau)) of Mycophenolate Mofetil | 48.255 hour* µg /ml | Standard Deviation 21.2246 |
90% CI: [0.899, 1.023]ANOVA
Primary
Maximum Observed Plasma Concentration (Cmax) of Mycophenolate Mofetil
Cmax was directly obtained from measured values of plasma concentrations.
Time frame: 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
Population: PK population. Two participants were excluded from the PK population: one dropped out of the study during the first period so had no PK samples. The other was omitted due to protocol violations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CellCept | Maximum Observed Plasma Concentration (Cmax) of Mycophenolate Mofetil | 16.189 µg /ml | Standard Deviation 9.9448 |
| Myfenax | Maximum Observed Plasma Concentration (Cmax) of Mycophenolate Mofetil | 14.308 µg /ml | Standard Deviation 8.3432 |
90% CI: [0.787, 0.968]ANOVA
Secondary
Degree of Fluctuation of the Concentration Levels of Mycophenolate Mofetil Over One Dosing Interval (PTF)
PTF was calculated as: (Cmax-Cmin)/(AUCt/t)\*100
Time frame: Day 14 and Day 28 (end of first two cross-over periods) before drug administration
Population: PK population. Two participants were excluded from the PK population: one dropped out of the study during the first period so had no PK samples. The other was omitted due to protocol violations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CellCept | Degree of Fluctuation of the Concentration Levels of Mycophenolate Mofetil Over One Dosing Interval (PTF) | 351.05 percentage of AUC for a dosing interval | Standard Deviation 161.195 |
| Myfenax | Degree of Fluctuation of the Concentration Levels of Mycophenolate Mofetil Over One Dosing Interval (PTF) | 323.67 percentage of AUC for a dosing interval | Standard Deviation 156.018 |
Secondary
Minimum Observed Plasma Concentration (Cmin) of Mycophenolate Mofetil
Cmin was directly obtained from measured values of plasma concentrations.
Time frame: 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
Population: PK population. Two participants were excluded from the PK population: one dropped out of the study during the first period so had no PK samples. The other was omitted due to protocol violations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CellCept | Minimum Observed Plasma Concentration (Cmin) of Mycophenolate Mofetil | 1.584 µg /ml | Standard Deviation 0.7801 |
| Myfenax | Minimum Observed Plasma Concentration (Cmin) of Mycophenolate Mofetil | 1.567 µg /ml | Standard Deviation 0.7387 |
90% CI: [0.877, 1.106]ANOVA
Secondary
Plasma Concentrations of Mycophenolate Mofetil in Pre-Administration Samples (Cpd)
Cpd was directly obtained from measured values of plasma concentrations.
Time frame: Day 14 and Day 28 (end of first two cross-over periods) before drug administration
Population: PK population. Two participants were excluded from the PK population: one dropped out of the study during the first period so had no PK samples. The other was omitted due to protocol violations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CellCept | Plasma Concentrations of Mycophenolate Mofetil in Pre-Administration Samples (Cpd) | 2.693 µg /ml | Standard Deviation 1.7001 |
| Myfenax | Plasma Concentrations of Mycophenolate Mofetil in Pre-Administration Samples (Cpd) | 3.001 µg /ml | Standard Deviation 2.0863 |
Secondary
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.
Time frame: Day 1 up to Day 112
Population: Safety population. One participant discontinued the study prior to Period II so the Myfenax # participants analyzed is one less than the CellCept arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CellCept | Summary of Participants With Adverse Events | Adverse Events | 15 participants |
| CellCept | Summary of Participants With Adverse Events | Related adverse events | 3 participants |
| CellCept | Summary of Participants With Adverse Events | Severe adverse events | 0 participants |
| CellCept | Summary of Participants With Adverse Events | Adverse events leading to discontinuation | 2 participants |
| CellCept | Summary of Participants With Adverse Events | Serious adverse events | 1 participants |
| CellCept | Summary of Participants With Adverse Events | Adverse events leading to death | 0 participants |
| Myfenax | Summary of Participants With Adverse Events | Adverse events leading to death | 0 participants |
| Myfenax | Summary of Participants With Adverse Events | Adverse Events | 17 participants |
| Myfenax | Summary of Participants With Adverse Events | Adverse events leading to discontinuation | 1 participants |
| Myfenax | Summary of Participants With Adverse Events | Serious adverse events | 1 participants |
| Myfenax | Summary of Participants With Adverse Events | Related adverse events | 7 participants |
| Myfenax | Summary of Participants With Adverse Events | Severe adverse events | 0 participants |
| Overall | Summary of Participants With Adverse Events | Related adverse events | 9 participants |
| Overall | Summary of Participants With Adverse Events | Severe adverse events | 0 participants |
| Overall | Summary of Participants With Adverse Events | Adverse events leading to death | 0 participants |
| Overall | Summary of Participants With Adverse Events | Adverse events leading to discontinuation | 3 participants |
| Overall | Summary of Participants With Adverse Events | Adverse Events | 26 participants |
| Overall | Summary of Participants With Adverse Events | Serious adverse events | 1 participants |
Secondary
Time Corresponding to Occurrence of Cmax (Tmax) of Mycophenolate Mofetil
Tmax was directly obtained from measured values.
Time frame: Day 14 and Day 28 (end of first two cross-over periods) before drug administration
Population: PK population. Two participants were excluded from the PK population: one dropped out of the study during the first period so had no PK samples. The other was omitted due to protocol violations.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CellCept | Time Corresponding to Occurrence of Cmax (Tmax) of Mycophenolate Mofetil | 1.119 hours | Standard Deviation 0.7462 |
| Myfenax | Time Corresponding to Occurrence of Cmax (Tmax) of Mycophenolate Mofetil | 1.344 hours | Standard Deviation 1.1439 |