Deconvoluting the in vitro to in vivo drug clearance gap: questioning the predictive performance of traditional hepatic clearance models

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Background and Purpose: In vitro to in vivo extrapolation (IVIVE) methods for hepatic clearance (CL H ) prediction often underpredict. This is partly due to reliance on mathematical models such as the well-stirred model (WSM) or the parallel tube model (PTM). The ex vivo isolated perfused rat liver (IPRL) model can bridge between in vitro and in vivo data, providing mechanistic understanding of the cause(s) of IVIVE shortcomings. Experimental Approach: This study evaluates the IPRL model for 16 compounds covering diversity in physicochemical properties, and benchmarks IPRL results against in vitro and in vivo data to verify the predictive performance of the WSM and PTM. Key Results: Results demonstrated that both the IPRL and in vivo clearance conflict with assumptions of the WSM or PTM, and instead represent a liver inlet clearance. Moreover, in vitro to ex vivo extrapolation underscores the limited performance of the WSM and PTM, especially for highly plasma protein bound compounds which are subject to sinusoidal hepatic uptake transport. Conclusion and Implications: This research experimentally reveals new insights into one of the root causes driving the limited performance of current IVIVE methods to predict CL H . While traditional IVIVE using the WSM or PTM is challenged by this evidence, mechanistic insights into the in vitro to in vivo clearance gap will support the optimization of IVIVE methods. Improved IVIVE strategies developed for rats can be translated to humans, leading to more accurate first-in-human dose predictions and better clinical trial efficacy and safety.

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