Predicting Hepatic Clearance

Over the course of lead optimisation, the Project Orion team synthesised more than 200 analogues across four chemical series targeting Kinase A. We will focus on thirteen representative compounds (MCF-001 through MCF-013) that illustrate the key PK lessons. In a real project, the full dataset would be much larger, but these thirteen cover the range of profiles a DMPK scientist encounters.

Before running expensive and time-consuming rat PK studies, we need to predict which of these compounds will have acceptable pharmacokinetics in vivo.

In vitro-in vivo extrapolation (IVIVE) is the process of translating test-tube measurements into predicted whole-animal PK parameters. The core translation uses CLint (intrinsic clearance) measured from two complementary in vitro systems: liver microsomes (capturing CYP-mediated oxidative metabolism) and hepatocytes (capturing a much broader range of hepatic clearance pathways including Phase II enzymes and transporters). These measurements are scaled to whole-liver capacity and fed into the well-stirred model to predict hepatic clearance. A parallel set of assays (Caco-2, PAMPA, solubility) predicts oral absorption.

The goal is not perfect prediction. It is triage: identifying compounds likely to fail (too high clearance, too low permeability, too poor solubility) and prioritising the most promising candidates for in vivo studies.