Pharmacokinetics of Generic to Brand Tacrolimus in Stable Renal Transplant Patients

• Dose-Normalized Area Under the Concentration-time Curve From Time 0 to 12 Hours (AUC0-12h) at Steady State [ 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. ] [ Designated as safety issue: No ]

  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 [ 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. ] [ Designated as safety issue: No ]
  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.

• Intra-patient Variability of Tacrolimus Pharmacokinetic Parameters [ Time Frame: Days 7 and 14, and Days 21 and 28. ] [ Designated as safety issue: No ]
  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 [ Time Frame: Days 14 and 28: predose ] [ Designated as safety issue: No ]
  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) [ Time Frame: 28 Days ] [ Designated as safety issue: No ]
  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 [ Time Frame: 28 Days ] [ Designated as safety issue: No ]

• To compare bioavailability of generic tacrolimus (Sandoz) to Prograf in stable renal transplant patients using the dose-normalized AUC0-12h and Cmax data [ Time Frame: 28 Days ] [ Designated as safety issue: No ]
• To evaluate intra-patient variability of tacrolimus pharmacokinetics of each formulation by comparing AUC0-12h, Cmax and C0 [ Time Frame: 28 Days ] [ Designated as safety issue: No ]
• To compare the C0 of generic tacrolimus (Sandoz) to Prograf [ Time Frame: 28 Days ] [ Designated as safety issue: No ]
• To present individual patient pharmacokinetic profiles [ Time Frame: 28 days ] [ Designated as safety issue: No ]
• To compare the total number of Adverse Events and Serious Adverse Events as a measure of safety [ Time Frame: 28 Days ] [ Designated as safety issue: No ]
• Number of reported Biopsy proven acute rejection episodes [ Time Frame: 28 Days ] [ Designated as safety issue: No ]

The study is designed to compare the pharmacokinetics of generic tacrolimus (Sandoz) to branded tacrolimus (Prograf) in stable renal transplant patients.

• Drug: Generic Tacrolimus
  Generic Sandoz tacrolimus supplied as capsules of 0.5 mg, 1 mg and 5 mg dose strengths.
  Other Name: Sandoz
• Drug: Branded Tacrolimus
  Capsules supplied at dose strengths of 0.5 mg, 1 mg, and 5 mg.
  Other Name: Prograf

• Experimental: Sequence 1 - Branded Tacrolimus / Generic Tacrolimus
  In Period 1 (Days 1-14) participants received branded tacrolimus (Prograf) orally twice a day and in Period 2 (Days 15 - 28) participants received generic tacrolimus (Sandoz) orally twice a day. Participants received the same stable dosage of tacrolimus they had been taking prior to enrollment (on a milligram for milligram basis).
  Interventions:

  • Drug: Generic Tacrolimus
  • Drug: Branded Tacrolimus
• Active Comparator: Sequence 2 - Generic Tacrolimus / Branded Tacrolimus
  In Period 1 (Days 1 - 14) participants received generic tacrolimus (Sandoz) orally twice a day and in Period 2 (Days 15 - 28) participants received branded tacrolimus (Prograf) orally twice a day. Participants received the same stable dosage of tacrolimus they had been taking prior to enrollment (on a milligram for milligram basis).
  Interventions:

  • Drug: Generic Tacrolimus
  • Drug: Branded Tacrolimus

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).