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

Abstract

ObjectiveThe 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. MethodsForty 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®; Chengdu Shengdi Medicine Co., Ltd.) and a reference tacrolimus (Astagraf XL®, 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. ResultsA 95% upper confidence bound was −0.05% for the peak concentration (Cmax), −0.02% for the AUC from 0 to the last time point (AUC0-t), and − 0.02% for the AUC from 0 to infinity (AUC0-∞). The geometric least square means ratio (test/reference) with 90% of confidence interval (CI)) was 96.10% (90.58%–101.95%) for Cmax, 93.80% (88.52%–99.39%) for AUC0-t, and 94.34% (89.20%–99.77%) for AUC0-∞. Meanwhile, the ratio of within-subject standard deviation of test/reference (σWT/WR) with 90% CI was 0.66 (0.50–0.86) for Cmax, 0.73 (0.55–0.96) for AUC0-t, and 0.75 (0.57–0.98) for AUC0-∞. 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. ConclusionGeneric tacrolimus (Ruibeirong®) is bioequivalent to branded tacrolimus (Astagraf XL®) with tolerable safety, which AUC predictive equations work well and are interchangeable between the two products.