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

Objective: The present study compared the pharmacokinetics of two (1 mg) tacrolimus formulations (test (generic from Panacea) and reference (innovator from Astellas)) 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 × 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) ng×h/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.