Predicting human pharmacokinetics from preclinical data: clearance

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 (CLH ) 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 CLH . Despite efforts in the laboratory steps, huge in vitro (predicted CLH )-in vivo (observed CLH ) discrepancy is not rare. A simple remedy to this discrepancy is to correct human predicted CLH using the ratio of in vitro-in vivo CLH obtained from animal species.