Randomized generic-sequence crossover pharmacokinetic study of innovator and two generic tacrolimus formulations in kidney transplant recipients according to CYP3A inhibitor co-administration

Abstract

Tacrolimus is a narrow therapeutic index immunosuppressant widely used in kidney transplantation. Although generic formulations reduce treatment costs, pharmacokinetic comparability under CYP3A inhibitor co-administration remains insufficiently studied. We conducted a prospective, open-label, three-period pharmacokinetic study in 24 stable kidney transplant recipients (KTRs), comprising a fixed innovator reference phase followed by a randomized two-period crossover of the two generic formulations with full 12-h pharmacokinetic profiling. Most participants (83.3%) were receiving CYP3A inhibitors. Relative to the innovator, geometric mean ratios (90% confidence intervals) for AUC 0–12 were 101.9% (93.5–103.0) for Generic A and 101.6% (96.8–106.6) for Generic B; corresponding C max ratios were 103.8% (96.9–111.2) and 104.8% (97.5–112.4). All intervals were within prespecified bioequivalence limits. Bioequivalence was also observed in booster-treated recipients, and no formulation-by-CYP3A5-genotype interaction was detected. An innovator-derived C0 + C2 + C4 equation showed strong cross-formulation prediction without coefficient re-estimation (R 2 = 0.978 for Generic A and 0.974 for Generic B). No adverse events or biopsy-proven rejection occurred during follow-up. These findings support the bioequivalence of the two evaluated generic formulations, including in stable recipients receiving CYP3A inhibitors. Trial registration : Thai Clinical Trials Registry (TCTR20251015001); Registration date 15/10/2025.