Bioequivalence evaluation and blood concentration estimation of generic and branded tacrolimus in healthy subjects under fasting: A randomized, four-periods, two-sequences, complete repeated, crossover study

Objective: The demand for generic tacrolimus is enormous. Our randomized trial was an open-label single-dose testing with four-periods and two-sequences; we aimed to evaluate the bioequivalence between a generic and branded tacrolimus by establishing their area under concentration-time curve (AUC) predictive equations. For better comparison, each tacrolimus served either as test vs. reference in sequence 1 or vice versa as reference vs. test in sequence 2.Methods: Forty healthy subjects were randomized into two groups, namely a sequence 1 group (N = 20 in test-reference-test-reference) or sequence 2 (N = 20, reference-test-reference-test) received a test tacrolimus (Ruibeirong (R); Chengdu Shengdi Medicine Co., Ltd.) and a reference tacrolimus (Astagraf XL (R), Astellas Ireland Co., Ltd.) under the fasting condition with a wash-out period of >= 14 days between every two phases. Blood samples were collected sequentially until 120 h after oral administration of tacrolimus.Results: A 95% upper confidence bound was -0.05% for the peak concentration (C-max), -0.02% for the AUC from 0 to the last time point (AUC(0-t)), and - 0.02% for the AUC from 0 to infinity (AUC(0-infinity)). The geometric least square means ratio (test/reference) with 90% of confidence interval (CI)) was 96.10% (90.58%-101.95%) for C-max, 93.80% (88.52%-99.39%) for AUC(0-t), and 94.34% (89.20%-99.77%) for AUC(0-infinity). Meanwhile, the ratio of within-subject standard deviation of test/reference (sigma(WT/WR)) with 90% CI was 0.66 (0.50-0.86) for C-max, 0.73 (0.55-0.96) for AUC(0-t), and 0.75 (0.57-0.98) for AUC(0-infinity). These results fulfilled the bioequivalence criteria by the Food and Drug Administration. Both products showed acceptable safety. Moreover, the AUC predictive equations (by linear regression plus limited sampling strategy) with 2-5 sampling time point showed the high performance (all R > 0.970, predictive error (PE) >0.5%, absolute PE <5.1%, which were interchangeable between test and reference products.Conclusion: Generic tacrolimus (Ruibeirong (R)) is bioequivalent to branded tacrolimus (Astagraf XL (R)) with tolerable safety, which AUC predictive equations work well and are interchangeable between the two products.