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

BackgroundTacrolimus 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.ObjectiveThe purpose of this study was to test the bioequivalence of generic (test) and innovator (reference) tacrolimus capsules.MethodsTwo 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 Cmax and AUC0–72 (0.5 mg) or AUC0–t (5 mg). Bioequivalence was assumed if the 90% CIs for the test/reference ratios of log-transformed Cmax and AUC values were within the limits specified by existing European guidelines. Data on safety and patient well-being were collected throughout the study.ResultsThe 90% CIs for 0.5 mg were 102.99%–120.80% for Cmax and 91.51%–105.92% for AUC0–72; those for 5 mg were 110.61%–120.96% for Cmax and 96.17%–103.55% for AUC0–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 Cmax and 90%–111% for AUC). There were no relevant differences in the safety profiles of the test and reference formulations.ConclusionsIn 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).