Bioequivalence of two tacrolimus 1-mg formulations under fasting conditions in healthy subjects: A randomized, two-period crossover trial

摘要

Objective: The present study compared the pharmacokinetics of two (1 mg) tacrolimus formulations (test (generic from Panacea) and reference (innovator from As-tellas)) after a single-dose administration as per the European Medicine Agency (EMA) guidelines to grant marketing authorization. Materials and methods: This study was a randomized. open-label, balanced, two-treatment, two-period, two-sequences, single-dose, truncated-area, crossover design with a washout period of 19 days between the phases. Healthy subjects aged 18 - 45 years (both inclusive) were included. Eligible subjects received a single oral dose of 5 x 1-mg capsule of tacrolimus either test or reference formulation. Blood samples were collected until 72.00 hours postdose, and peak concentration (C-max) and area under the curve (AUC(0-72)) were evaluated in whole blood using validated LC-MS/MS. Safety was also assessed in each period. Results: Of 56 subjects enrolled, 52 completed both study periods. The arithmetic mean (SD) C-max for the reference and test formulations was 40.62 (11.30) and 46.20 (10.73) ng/mL, and AUC(0-72) was 348.34 (156.41) and 361.04 (158.71) ngxh/mL, respectively. The geometric least square mean ratio (90% confidence interval (CI)) was 115.07% (90% CI: 109.81, 120.59) for C-max and 103.78 (90% CI: 97.40, 110.58) for AUC(0-72), which fell within the acceptance range as per EMA guidelines for narrow therapeutic index drugs (C-max: 80.00 - 125.00%; AUC: 90.00 - 111.11%). No serious adverse event was observed. Conclusion: The generic tacrolimus was bioequivalent to the reference formulation, was well tolerated, and provides a well-acceptable alternative to the reference drug. Switching treatment to generic tacrolimus medication may reduce the cost and economic burden of treating transplanted patients.