Using Physiologically Based Pharmacokinetic Modeling to Assess the Risks of Failing Bioequivalence Criteria: a Tale of Two Ibuprofen Products.

ABSTRACT

The aims of the proposed study were to develop and verify a quantitative model-based framework to anticipate the in vivo bioequivalence of ibuprofen immediate release formulations. This stepwise approach integrated virtual bioequivalence trials to simulate the test to reference (T/R) ratio for positive (i.e., bioequivalent) and negative (i.e., non-bioequivalent) control formulations containing ibuprofen, approximated distribution of interoccasion variability (IOV) on ibuprofen peak (Cmax) and extent of exposure (AUC) by bootstrapping resampling methods, post hoc incorporation of IOV to simulated T/R ratios, and power curve analysis. After post hoc incorporation of the bootstrapped IOV to the simulated Cmax T/R geometric mean ratios, the resulting 90% confidence intervals overlapped with the in vivo observations for both pairwise comparisons. On the other hand, simulated and observed AUC TNBE/R geometric mean ratios differed, likely due to the lack of propagating clearance-related IOV to the simulations. This approach is in line with modern regulatory initiatives that advocate leveraging quantitative methods and modeling to modernize generic drug development and review. Graphical abstract.