Abstract

Bioequivalence (BE) studies support the approval and clinical use of both new drug and generic drug products. Virtual BE studies have been conducted using physiologically based pharmacokinetic absorption models (PBPK AMs) to aid the evaluations of generic drug products. The aim of the current study is to determine the dissolution boundary for maintaining BE between the test and reference oseltamivir phosphate (OP) drug products using the PBPK AM–based virtual BE studies in adults and pediatrics. The adult PBPK AM for OP and its metabolite oseltamivir carboxylate (OC) are developed and verified/validated using intravenous and oral data from multiple generic OP products. The pediatric PBPK AM is extrapolated from the adult PBPK AM. The virtual BE analysis is conducted using simulated PK profiles from the reference products and the generic products with theoretical dissolution profiles as inputs. Results indicate that the generic products with 10% slower dissolution profile than the pivotal reference bio-batch could still maintain BE to the reference in adults. In contrast, a stringent trend of dissolution boundary is observed for pediatrics (6% slower for adolescents, 4% slower for 0–2-month neonates) to maintain BE. This study addresses the important applications of PBPK AM in evaluating BE in different age populations, mitigating risk of formulation/batch changes, and providing a quantitative basis for setting clinically relevant dissolution specifications for OP and OC in both adults and pediatrics.

By Lei Miao, Youssef M. Mousa, Liang Zhao, Kimberly Raines, Paul Seo & Fang Wu