Chapter 9: Mechanistic Modelling to Predict Transporter-mediated Drug Disposition and Drug–Drug Interactions
Published:16 Aug 2016
R. Li, K. K. Machavaram, S. Thomas, and M. V. Varma, in Drug Transporters: Volume 1: Role and Importance in ADME and Drug Development, ed. G. Nicholls, K. Youdim, G. Nicholls, and K. Youdim, The Royal Society of Chemistry, 2016, vol. 1, ch. 9, pp. 333-360.
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Emphasis is placed within drug discovery and development on the assessment of transporter activity with regard to clearance and dose predictions, and to evaluate pharmacokinetic variability associated with drug–drug interactions (DDIs) and genetic variants. Additionally, drug transporters may regulate the target tissue exposure and consequently regulate the pharmacological and/or toxicological responses. Notable progress has been made in the development of in vitro techniques to facilitate characterization of transporter affinities (substrate or inhibitor) and kinetics. Mechanistic predictions utilizing physiologically based pharmacokinetic modeling are increasingly being used to evaluate the contribution of a transporter and delineate the transporter–enzyme interplay on the basis of hypothesis driven functional in vitro findings. However, challenges exist in the quantitative in vitro–in vivo extrapolation of transporter kinetics due to the limited quantitative information on their absolute abundance and an incomplete understanding of the functional mechanisms of both in vitro and in vivo transport processes. This chapter reviews the state of the model based approaches to estimate in vitro transporter kinetic parameters, and to predict clinical pharmacokinetics and the associated DDIs of transporter substrates.