Assessment of the Kochak-Benet Equation for Hepatic Clearance for the Parallel-Tube Model: Relevance of Classic Clearance Concepts in PK and PBPK.

This report reviews concepts related to operation of the classic parallel-tube model (PTM) for hepatic disposition and examines two recent proposals of a newly derived equation to describe hepatic clearance (CLH). It is demonstrated that the proposed equation is identical to a re-arrangement of an earlier relationship from Pang and Rowland and provides a means of calculation of intrinsic clearance (CLint,PTM) rather than CLH as posed. We further demonstrate how classic hepatic clearance models with an assumed CLint, while subject to numerous limitations, remain highly useful and necessary in both traditional pharmacokinetics (PK) and physiologically based pharmacokinetic (PBPK) modeling.