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Using a Physiologically Based Pharmacokinetic Absorption Model to Establish Dissolution Bioequivalence Safe Space for Oseltamivir in Adult and Pediatric Populations

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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.

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Acknowledgments

This project is supported by US Food and Drug Administration MCMi funded Oak Ridge Institute for Science and Education (ORISE) Fellowships. Drs. Lei Miao and Youssef Mousa were supported by an appointment to the Research Participation Program at CDER, administered by ORISE through an interagency agreement between the US Department of Energy and the FDA.

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Authors and Affiliations

  1. Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA

    Lei Miao, Youssef M. Mousa, Liang Zhao & Fang Wu

  2. Division of Biopharmaceutics, Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA

    Kimberly Raines & Paul Seo

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  1. Lei Miao
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  2. Youssef M. Mousa
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Correspondence to Fang Wu.

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Miao, L., Mousa, Y.M., Zhao, L. et al. Using a Physiologically Based Pharmacokinetic Absorption Model to Establish Dissolution Bioequivalence Safe Space for Oseltamivir in Adult and Pediatric Populations. AAPS J 22, 107 (2020). https://doi.org/10.1208/s12248-020-00493-6

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