Bioequivalence of Two Tacrolimus Formulations Under Fasting Conditions in Healthy Male Subjects

Abstract 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).