Pharmacokinetics in Drug Discovery: An Exposure-Centred Approach to Optimising and Predicting Drug Efficacy and Safety

Handbook of Experimental Pharmacology
Andreas Reichel, Philip Lienau

Abstract

The role of pharmacokinetics (PK) in drug discovery is to support the optimisation of the absorption, distribution, metabolism and excretion (ADME) properties of lead compounds with the ultimate goal to attain a clinical candidate which achieves a concentration-time profile in the body that is adequate for the desired efficacy and safety profile. A thorough characterisation of the lead compounds aiming at the identification of the inherent PK liabilities also includes an early generation of PK/PD relationships linking in vitro potency and target exposure/engagement with expression of pharmacological activity (mode-of-action) and efficacy in animal studies. The chapter describes an exposure-centred approach to lead generation, lead optimisation and candidate selection and profiling that focuses on a stepwise generation of an understanding between PK/exposure and PD/efficacy relationships by capturing target exposure or surrogates thereof and cellular mode-of-action readouts in vivo. Once robust PK/PD relationship in animal PD models has been constructed, it is translated to anticipate the pharmacologically active plasma concentrations in patients and the human therapeutic dose and dosing schedule which is also based on the predi...Continue Reading

Citations

Dec 12, 2018·The American Journal of Chinese Medicine·Xiuping ChenJingshan Shi
Apr 18, 2019·Clinical Pharmacology and Therapeutics·Alexandre J S RibeiroDavid G Strauss
Sep 18, 2020·Experimental Biology and Medicine·Keri Dame, Alexandre Js Ribeiro
Jan 27, 2021·Planta medica·Byoung Hoon YouYoung Hee Choi
Aug 25, 2021·Nature Reviews. Chemistry·Marcus MiethkeRolf Müller

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