Renal Transplant
Conditions
Keywords
Renal transplant, kidney transplant, immunosuppressive therapy, anti-rejection medication, pharmacokinetics, tacrolimus
Brief summary
The study is designed to compare the pharmacokinetics of generic tacrolimus (Sandoz) to branded tacrolimus (Prograf) in stable renal transplant patients.
Interventions
Generic Sandoz tacrolimus supplied as capsules of 0.5 mg, 1 mg and 5 mg dose strengths.
DRUGBranded Tacrolimus
Capsules supplied at dose strengths of 0.5 mg, 1 mg, and 5 mg.
Sponsors
Sandoz
Novartis
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
* Able to participate and willing to give written informed consent and to comply with the study visits and restrictions. * Patient who has received a primary or secondary kidney transplant * Patient who is at least 6 months post transplant and on a stable dose of tacrolimus as defined by physician, one tacrolimus trough level within the physician defined target range within past 6 months and one additional trough level during the screening period within 30% of the physician defined target range. * Body mass index (BMI) greater than or equal to 19 but less than or equal to 35 * Patients who are taking tacrolimus (generic, Sandoz) or Prograf
Exclusion criteria
* Evidence of any acute rejection * Patients who require dialysis within 6 months prior to study entry * Recipients of antibodies blood group (ABO) incompatible allograft or positive crossmatch * Recipients of multiple organ transplants * Patients who have tested positive for hepatitis B surface antigen (HBsAG) or human immunodeficiency virus (HIV), or who are recipients of organ from donors who are known to be HBsAG or HIV positive. Virology screening at the time of transplant was acceptable unless more recent tests were available. * History of malignancy, treated or untreated, within the past 2 years with the exception of carcinoma in situ or excised basal cell carcinoma * Glomerular filtration rate ≤35 ml/min measured by modification of diet in renal disease (MDRD4) * No anticipated change in the immunosuppressive regimen during patient participation other than that required by the protocol * Initiation of any medications that could interfere with tacrolimus blood levels, including over the counter medications, herbal supplements, grapefruit or grapefruit juice. * Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (\> 5 mIU/mL) * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are * women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner * women whose partners have been sterilized by vasectomy or other means * using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives, and some intrauterine devices (IUDs); periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable. * Patients who are taking a generic tacrolimus product other than tacrolimus (generic, Sandoz).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Normalized Area Under the Concentration-time Curve From Time 0 to 12 Hours (AUC0-12h) at Steady State | Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing. | Dose-normalized area under the concentration-time curve from time 0 to 12 hours (AUC0-12h) at steady state after 14 days of treatment with each study drug. Geometric mean and 95% confidence intervals were determined from an analysis of variance (ANOVA) model for the dose-normalized log transformed values with treatment, period and sequence as fixed factors and patients nested within sequences as a random factor. |
| Dose-normalized Maximum Plasma Drug Concentration (Cmax) at Steady State | Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing. | Maximum (peak) plasma drug concentration after drug administration at steady state (after 14 days of treatment with each study drug). Geometric mean and 95% confidence intervals were determined from an analysis of variance (ANOVA) model for the dose-normalized log transformed values with treatment, period and sequence as fixed factors and patients nested within sequences as a random factor. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters | Days 7 and 14, and Days 21 and 28. | The intra-patient variability of tacrolimus pharmacokinetics of each formulation was evaluated by comparing AUC0-12h, maximum drug concentration (Cmax) and trough drug concentration (C0) at Days 7 and 14, and Days 21 and 28. Intra-patient variability was assessed by a calculation of the coefficient of variation, by patient, using the repeated measurements within each Period, where the coefficient of variation (%) = standard deviation/mean\*100. |
| Trough Plasma Drug Concentration (C0) at Steady State | Days 14 and 28: predose | Trough plasma drug concentration measured prior to drug administration at steady state (after 14 days of treatment with each study drug). |
| Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | 28 Days | An AE was defined as the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event was not considered to be related to study drug. An SAE was an event which: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; required or prolonged inpatient hospitalization; was medically significant, i.e., an event that jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above. |
| Number of Participants With Reported Biopsy Proven Acute Rejection Episodes | 28 Days | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants Period 1 (Days 1 through 14): Participants randomized to Sequence 1 took branded tacrolimus (Prograf) and participants randomized to Sequence 2 took generic tacrolimus (Sandoz).
Period 2 (Days 15 through 28): Participants randomized to Sequence 1 crossed over to treatment with generic tacrolimus and participants randomized to Sequence 2 crossed over to treatment with branded tacrolimus. | 71 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Protocol deviation | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age Continuous | 52.1 years STANDARD_DEVIATION 12.5 |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 71 | 4 / 71 |
| serious Total, serious adverse events | 0 / 71 | 1 / 71 |
Outcome results
Primary
Dose-Normalized Area Under the Concentration-time Curve From Time 0 to 12 Hours (AUC0-12h) at Steady State
Dose-normalized area under the concentration-time curve from time 0 to 12 hours (AUC0-12h) at steady state after 14 days of treatment with each study drug. Geometric mean and 95% confidence intervals were determined from an analysis of variance (ANOVA) model for the dose-normalized log transformed values with treatment, period and sequence as fixed factors and patients nested within sequences as a random factor.
Time frame: Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing.
Population: Pharmacokinetic (PK) analysis set included the subset of patients from the Full Analysis Set (all patients to whom study medication had been assigned) with evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Generic Tacrolimus | Dose-Normalized Area Under the Concentration-time Curve From Time 0 to 12 Hours (AUC0-12h) at Steady State | 51.73 ng*hr/mL/mg |
| Branded Tacrolimus | Dose-Normalized Area Under the Concentration-time Curve From Time 0 to 12 Hours (AUC0-12h) at Steady State | 50.58 ng*hr/mL/mg |
95% CI: [0.96, 1.09]
Comparison: To compare the bioavailability of generic tacrolimus to branded tacrolimus, the 90% confidence intervals of the ratios of geometric means of AUC0-12h were assessed relative to the interval \[80%, 125%\].p-value: 0.48690% CI: [0.97, 1.08]ANOVA
Primary
Dose-normalized Maximum Plasma Drug Concentration (Cmax) at Steady State
Maximum (peak) plasma drug concentration after drug administration at steady state (after 14 days of treatment with each study drug). Geometric mean and 95% confidence intervals were determined from an analysis of variance (ANOVA) model for the dose-normalized log transformed values with treatment, period and sequence as fixed factors and patients nested within sequences as a random factor.
Time frame: Days 14 and 28: Predose and at 0.5, 1, 1.5, 1.75, 2, 3, 4, 8 and 12 hours after dosing.
Population: Pharmacokinetic (PK) analysis set included the subset of patients from the Full Analysis Set (all patients to whom study medication had been assigned) with evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Generic Tacrolimus | Dose-normalized Maximum Plasma Drug Concentration (Cmax) at Steady State | 8.34 ng/mL/mg |
| Branded Tacrolimus | Dose-normalized Maximum Plasma Drug Concentration (Cmax) at Steady State | 7.62 ng/mL/mg |
95% CI: [1, 1.2]
Comparison: To compare the bioavailability of generic tacrolimus to branded tacrolimus, the 90% confidence intervals of the ratios of geometric means of Cmax were assessed relative to the interval \[80%, 125%\].p-value: 0.05790% CI: [1.01, 1.18]ANOVA
Secondary
Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters
The intra-patient variability of tacrolimus pharmacokinetics of each formulation was evaluated by comparing AUC0-12h, maximum drug concentration (Cmax) and trough drug concentration (C0) at Days 7 and 14, and Days 21 and 28. Intra-patient variability was assessed by a calculation of the coefficient of variation, by patient, using the repeated measurements within each Period, where the coefficient of variation (%) = standard deviation/mean\*100.
Time frame: Days 7 and 14, and Days 21 and 28.
Population: PK Analysis set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Generic Tacrolimus | Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters | C0 | 13.24 percent coefficient of variation | Standard Error 9.766 |
| Generic Tacrolimus | Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters | AUC0-12h | 13.41 percent coefficient of variation | Standard Error 10.438 |
| Generic Tacrolimus | Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters | Cmax | 16.92 percent coefficient of variation | Standard Error 15.485 |
| Branded Tacrolimus | Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters | C0 | 11.07 percent coefficient of variation | Standard Error 10.285 |
| Branded Tacrolimus | Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters | AUC0-12h | 11.02 percent coefficient of variation | Standard Error 9.756 |
| Branded Tacrolimus | Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters | Cmax | 17.86 percent coefficient of variation | Standard Error 14.874 |
Secondary
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
An AE was defined as the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event was not considered to be related to study drug. An SAE was an event which: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; required or prolonged inpatient hospitalization; was medically significant, i.e., an event that jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above.
Time frame: 28 Days
Population: Safety set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Generic Tacrolimus | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Serious adverse event | 0 participants |
| Generic Tacrolimus | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Any adverse event | 8 participants |
| Branded Tacrolimus | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Any adverse event | 12 participants |
| Branded Tacrolimus | Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Serious adverse event | 1 participants |
Secondary
Number of Participants With Reported Biopsy Proven Acute Rejection Episodes
Time frame: 28 Days
Population: Full analysis set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Generic Tacrolimus | Number of Participants With Reported Biopsy Proven Acute Rejection Episodes | 0 participants |
| Branded Tacrolimus | Number of Participants With Reported Biopsy Proven Acute Rejection Episodes | 0 participants |
Secondary
Trough Plasma Drug Concentration (C0) at Steady State
Trough plasma drug concentration measured prior to drug administration at steady state (after 14 days of treatment with each study drug).
Time frame: Days 14 and 28: predose
Population: PK analysis set, where data were available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Generic Tacrolimus | Trough Plasma Drug Concentration (C0) at Steady State | Day 14 [N= 34, 33] | 7.25 ng/mL | Standard Deviation 1.58 |
| Generic Tacrolimus | Trough Plasma Drug Concentration (C0) at Steady State | Day 28 [N=31, 33] | 7.26 ng/mL | Standard Deviation 2.091 |
| Branded Tacrolimus | Trough Plasma Drug Concentration (C0) at Steady State | Day 28 [N=31, 33] | 7.04 ng/mL | Standard Deviation 2.379 |
| Branded Tacrolimus | Trough Plasma Drug Concentration (C0) at Steady State | Day 14 [N= 34, 33] | 7.01 ng/mL | Standard Deviation 1.694 |