Using a Physiologically Based Pharmacokinetic Absorption Model to Establish Dissolution Bioequivalence Safe Space for Os
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Research Article Using a Physiologically Based Pharmacokinetic Absorption Model to Establish Dissolution Bioequivalence Safe Space for Oseltamivir in Adult and Pediatric Populations Lei Miao,1 Youssef M. Mousa,1 Liang Zhao,1 Kimberly Raines,2 Paul Seo,2 and Fang Wu1,3
Received 4 March 2020; accepted 28 July 2020 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. KEY WORDS: bioequivalence; dissolution; oseltamivir; pediatric; physiologically based pharmacokinetic absorption model.
INTRODUCTION To ensure therapeutic equivalency, generic drugs or new drug products from different manufacturing batches are required to have equivalent rate and extent of absorption to their reference products (1). Bioequivalence (BE) studies are widely accepted and play a crucial role in supporting the approval and marketing of both generic and new drug products (2). Generally, in vivo BE studies
Parts of the results were presented at the American Association of Pharmaceutical Scientists (AAPS) 2019 PharmSci 360 Annual Conference in San Antonio in Texas. 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. 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. 3 To whom correspondence should be addressed. (e–mail: Fang.
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