Predicting human pharmacokinetics from preclinical data: clearance

Dong-Seok Yim; Soo Hyeon Bae; Suein Choi

doi:10.12793/tcp.2021.29.e12

Predicting human pharmacokinetics from preclinical data: clearance

Transl Clin Pharmacol. 2021 Jun;29(2):78-87. doi: 10.12793/tcp.2021.29.e12. Epub 2021 Jun 22.

Authors

Dong-Seok Yim^{1

2}, Soo Hyeon Bae³, Suein Choi^{1

2}

Affiliations

¹ Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
² PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
³ Qfitter Inc., Seoul 06578, Korea.

Abstract

We have streamlined known in vitro methods used to predict the clearance (CL) of small molecules in humans in this tutorial. There have been many publications on in vitro methods that are used at different steps of human CL prediction. The steps from initial intrinsic CL measurement in vitro to the final application of the well-stirred model to obtain predicted hepatic CL (CL_H) are somewhat complicated. Except for the experts on drug metabolism and PBPK, many drug development scientists found it hard to figure out the entire picture of human CL prediction. To help readers overcome this barrier, we introduce each method briefly and demonstrate its usage in the chain of related equations destined to the CL_H. Despite efforts in the laboratory steps, huge in vitro (predicted CL_H)-in vivo (observed CL_H) discrepancy is not rare. A simple remedy to this discrepancy is to correct human predicted CL_H using the ratio of in vitro-in vivo CL_H obtained from animal species.

Keywords: Clearance; Human Prediction; Small Molecule; Translation.