Measures of Exposure versus Measures of Rate and Extent of Absorption
Regulatory assessment of bioavailability and bioequivalence in the US frequently relies on measures of rate and extent of absorption. Rate of absorption is not only difficult to measure but also bears little clinical relevance. This paper proposes that measures of bioavailability and bioequivalence for drugs that achieve their therapeutic effects after entry into the systemic circulation are best expressed in terms of early [partial area under the concentration-time curve (AUC)], peak plasma or serum drug concentration and total AUC exposure for a plasma or serum concentration-time profile. With suitable documentation, these systemic exposure measures can be related to efficacy and tolerability outcomes. The early measure is recommended for an immediate release drug product where a better control of drug absorption is needed, for example to ensure rapid onset of a therapeutic effect or to avoid an adverse reaction from a fast input rate. The 3 systemic exposure measures for bioavailability and bioequivalence studies can provide critical links between product quality and clinical outcome and thereby reduce the current emphasis on rate of absorption.
KeywordsMean Residence Time Reference Product Bioequivalence Study Absorption Rate Constant Partial Area
The authors wish to acknowledge Drs Thomas Tozer, Frederic Bois, Laszlo Endrenyi, Michael Fossler, Alfred Balch, Chuanpu Hu, William Gillespie, Donald Schuirmann, Rabindra Patnaik and Dale Conner, as well as the members of the FDA Metrics Working Group for their contributions to the deliberation of this topic. The current members of the FDA Metrics Working Group are Mei-Ling Chen (Chair), Barbara Devit, Mamata Gokhale, Yih-Chain Huang, Ajaz Hussain, Peter Lee, Zakaria Wahba and Dan Wang.
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