Is Bioequivalence Established Based on the Reference-Scaled Average Bioequivalence Approach Relevant to Chronic Administration of Phenytoin? Perspectives Based on Population Pharmacokinetic Modeling and Simulations.

Abstract

Phenytoin demonstrates time-dependent and nonlinear pharmacokinetics (PK) within the therapeutic range of 10 to 20 μg/mL. There are discussions on the relevance of bioequivalence (BE) demonstrated in a single-dose BE study in healthy subjects to exposure under chronic use conditions in patients, particularly given that phenytoin has a narrow therapeutic index. The objective of this study was to quantitatively evaluate the appropriateness of single-dose PK BE through simulations for the phenytoin extended-capsule products. A previously published population PK model was updated to account for the interoccasion variability using the dense PK data of the reference listed drug (Dilantin) from 5 single-dose, fully replicated BE studies (n = 124). BE studies with alternative designs were simulated using the developed PK model and subsequently analyzed accordingly: Scenario 1, multiple-dose, 2-period, crossover BE studies with an average BE approach; Scenario 2, single-dose, 4-period, fully replicated BE studies with a reference-scaled average BE approach as recommended in the product-specific guidance. In both scenarios, hypothetical phenytoin capsules with different formulation-related PK parameters, such as relative bioavailability and absorption rates, were included in the simulations. The results showed that the both scenarios provided the same results with respect to BE conclusions.