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Physiologically Based Pharmacokinetic Modeling to Evaluate Formulation Factors Influencing Bioequivalence of Metoprolol Extended‐Release Products
Author(s) -
Basu Sumit,
Yang Haitao,
Fang Lanyan,
GonzalezSales Mario,
Zhao Liang,
Trame Mirjam N.,
Lesko Lawrence,
Schmidt Stephan
Publication year - 2019
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1017
Subject(s) - bioequivalence , metoprolol , pharmacokinetics , pharmacology , drug , absorption (acoustics) , medicine , bioavailability , dissolution testing , materials science , anesthesia , biopharmaceutics classification system , composite material
The University of Florida Center for Pharmacometrics and Systems Pharmacology and the Food and Drug Administration Office of Generic Drugs have collaborated on a research project to develop a mechanism‐ and risk‐based strategy that systematically investigates postmarketing reports of therapeutic inequivalence following the switch between brand and generic drug products. In this study we developed and qualified a physiologically based pharmacokinetic model to systematically investigate the influence of drug‐ and formulation‐related properties on the oral absorption and bioequivalence of modified‐release products using metoprolol as an example. Our findings show that the properties of the release‐controlling polymer are the critical attributes for in vitro dissolution, in vivo absorption, and systemic exposure (ie, pharmacokinetics) and, thus, the bioequivalence of metoprolol extended‐release products rather than the properties of the drug itself. Differences in dissolution rate can result in significant differences in maximum plasma concentration but not in area under the concentration‐time curve.