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Difficulties in prediction of in vivo clearance

Successful and Unsuccessful Prediction of Human Hepatic Clearance for Lead Optimization

Here’s a great paper published by Jasleen Sodhi and Leslie Benet discussing the difficulties surrounding the prediction of in vivo clearance, in particular the IVIVE (in vitro to in vivo extrapolation) underprediction which can vary significantly from drug-to-drug.

Hepatic clearance largely determines the exposure of drug in the body, influencing both the efficacy and safety of a new drug, and thus it’s important to get the prediction correct! IVIVE is the most commonly employed methodology to predict hepatic clearance.

The paper covers common in vitro techniques used to predict hepatic clearance as well as current challenges and recent theoretical advancements in IVIVE. The authors identified a CYP3A4 underprediction anomaly where microsomes result in markedly higher CLint values and IVIVE success than hepatocytes, but the same trend was not observed for other CYP isoforms.

The authors propose that current approaches do not account for the pharmacokinetic volume of distribution that can vary for each drug, highlighting that the liver is not a one-compartment homogenous system.

Reference:

Successful and Unsuccessful Prediction of Human Hepatic Clearance for Lead Optimization

Jasleen K. Sodhi and Leslie Z. Benet

Journal of Medicinal Chemistry 2021 64 (7), 3546-3559

DOI: 10.1021/acs.jmedchem.0c01930

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