Comparative bioequivalence of 1 mg and 4 mg tacrolimus extended-release tablets: randomized, open label, fully replicate, crossover trials in healthy adult subjects

Introduction These studies were planned to establish bioequivalence between two doses (1-mg and 4-mg) of test product (tacrolimus extended-release tablets manufactured by Intas Pharmaceuticals Ltd., India) with reference product (Envarsus XR ® manufactured for Veloxis Pharmaceuticals, Inc., USA). Methods These were open-label, randomized, two-treatments, four-periods, two-sequence, oral single-dose, fully-replicate, crossover trials in healthy subjects under fasting and fed conditions. The study included subjects aged 18–45 years, with a body mass index of 18.5-29.9 kg/m 2 . Bioequivalence was assessed based on key pharmacokinetic parameters (AUC, C max , T max and t 1/2 ). Safety and tolerability were assessed by monitoring adverse events (AEs), serious AEs and death. Results The analysis set included a total of 85 (1-mg fasting), 83 (1-mg fed), 85 (4-mg fasting), and 85 (4-mg fed) subjects. Similar demographics were observed across all subjects. Results showed comparable C max , T max , AUC 0-t , AUC 0-∞ and t ½ for 1-mg and 4mg mg test vs. reference product under fasting and fed conditions. The upper limit of 90% confidence intervals for within subject standard deviation for test product/within subject standard deviation for reference product (σWT/σWR), 95% upper confidence bound, and 90% confidence intervals for C max , AUC 0–t , and AUC 0–∞ were within the corresponding acceptance criteria as per EMA and met all the bioequivalence criteria. Conclusion The developed tacrolimus test product (1-mg and 4-mg) was bioequivalent to the reference product, was well-tolerated, and provided a well-acceptable alternative to the reference product. These studies were performed in healthy individuals, further studies in transplant patient populations to confirm clinical applicability are warranted. CTRI number These studies have not been registered on the CTRI portal. The studies are routine BA/BE studies conducted in healthy volunteers. As per prevailing regulatory guidance, CTRI registration is not mandatory for such normal BA/BE studies. Additionally, the product under evaluation is already approved worldwide, and the studies do not constitute interventional clinical trials in patients.