Application of New Bioequivalence Testing Procedures To Tacrolimus Formulations in Stable Kidney Recipients: Global Regulatory Impact.

Abstract

Bioequivalence(BE) studies are an integral component of innovator and generic drug approval processes. Worldwide regulatory bodies have and continue to modify BE testing approaches for narrow therapeutic index(NTI) drugs such as tacrolimus. Modifications of BE approaches for NTI drugs essentially include two approaches 1)Direct tightening of average BE limits and 2) reference scaled average BE(RSCABE) based upon the within subject variability of the innovator product in healthy volunteers. The transplant community has encouraged testing in the transplant population. A recent publication of a prospective, two-center, randomized, two-period, two sequence, crossover, steady-state pharmacokinetic study comparing Sandoz generic tacrolimus (TS) vs Prograf (TP) in stable renal transplants revealed the following. The TS:TP ratio for AUC 0-12 was 1.02 with a 90% CI of 97-108% and Cmax was 1.09 with a 90% CI of 101-118%. Methods: Various BE testing approaches were applied to these data in stable renal transplants including tighter BE limits and RSCABE. Results: In the renal transplant population, tighter average BE limits for most regulatory bodies (Health Canada, South Africa, Asia and Latin America) were met for AUC and Cmax, however the Cmax did not meet 2010 regulatory standards of the EMA and the Danish Medicine Agency due to Cmax CI outside the 90.0-111.11% approval range and by not including 100% respectively. However in 2013, the EMA Efficacy Working Party recommended acceptable Cmax CI for tacrolimus of 80-125%. Calculations for RSCABE resulted in within subject variability of the innovator product (TP) of 14.9% and 24.2% for AUC and Cmax respectively. Using the RSCABE procedure, the 90% CI to meet BE standards for AUC was 86-117% and Cmax was 80-125%. Conclusion: TS in renal transplants met all current FDA and EMA modified bioequivalence criteria. Also, application of RSCABE to the variability of 24.2% of TP Cmax in the renal transplants showed that the confidence interval of 80-125% is acceptable and allows for adjustment to the variability of the innovator product, TP, in transplant recipients. The RSCABE approach dynamically adjusts to the variability of tacrolimus PK parameters of renal transplants, and may be more appropriate than fixed BE acceptance limits. DISCLOSURES:Wiland, A.: Employee, Novartis. McCague, K.: Employee, Novartis.