Bioequivalence of two tacrolimus formulations under fasting conditions in healthy male subjects.

Background: Tacrolimus is a macrolide immunosuppressant indicated for prophylaxis of transplant rejection. The European regulatory authorities require comparative bioavailability studies with an innovator product to grant marketing authorization of generic products.

Objective: The purpose of this study was to test the bioequivalence of generic (test) and innovator (reference) tacrolimus capsules.

Methods: Two open-label, 2-period, single-dose, crossover studies compared 0.5 mg and 5 mg capsule test formulations of tacrolimus with reference products in fasting, healthy male volunteers. The 2 study periods were separated by a 20-day (0.5 mg) or 21-day (5 mg) washout period. Blood samples were collected for up to 72 (0.5 mg) or 192 (5 mg) hours post-dose. Tacrolimus concentrations in whole blood were determined using a validated LC-MS/MS method. The primary evaluation criteria were C(max) and AUC(0-72) (0.5 mg) or AUC(0-t) (5 mg). Bioequivalence was assumed if the 90% CIs for the test/reference ratios of log-transformed C(max) and AUC values were within the limits specified by existing European guidelines. Data on safety and patient well-being were collected throughout the study.

Results: The 90% CIs for 0.5 mg were 102.99%-120.80% for C(max) and 91.51%-105.92% for AUC(0-72); those for 5 mg were 110.61%-120.96% for C(max) and 96.17%-103.55% for AUC(0-t). These values meet the requirements for assuming bioequivalence as defined in the European Medicines Agency guidelines for narrow therapeutic index drugs (80%-125% for C(max) and 90%-111% for AUC). There were no relevant differences in the safety profiles of the test and reference formulations.

Conclusions: In these comparative bioavailability studies of fasting, healthy male volunteers, the test and reference formulations of tacrolimus 0.5 mg and 5 mg capsules were well tolerated and met the requirements of the European regulatory bioequivalence guidelines. Both studies have been submitted for registration with Clinical Trials Registry-India: CTRI application references REF/2011/05/002346 (0.5 mg) and REF/2011/05/002347 (5 mg).