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bioRxiv · 10.1101/2020.10.09.332460

Virtual experiments provide plausible explanations for IVIVE underpredictions of hepatic clearance

Krishnan, P.·Smith, A. K.·Ropella, G. E. P.·Dutta, L.·Kennedy, R. C.·Hunt, C. A.
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Abstract

We explore a virtual experiment strategy to discover plausible mechanism-based explanations for frequently inaccurate predictions of hepatic drug clearance made using established in vitro-in vivo extrapolation methods. We describe a three-protocol plan that uses validated software analogs of real in vitro and in vivo systems constructed using a common set of objects, components, spaces, and methods. Both systems utilize identical quasi-autonomous hepatocyte analogs containing enzyme-like objects. We parameterize concrete mobile objects (virtual compounds) to simulate the referent drugs disposition and removal characteristics in vitro and in vivo. The goal of Protocol one (Protocol two) is that measures of virtual compound removal using the in vitro analog (in vivo analog) map directly to the measurements used to compute intrinsic clearance (in vivo hepatic clearance). Protocol three, the focus of this work, requires achieving an essential cross-system validation target. For a subset of virtual compounds, measurements of unbound compounds entering hepatocytes (and their subsequent removal) during virtual in vitro experiments will directly predict corresponding measures made during virtual in vivo experiments. We study four highly permeable virtual compounds when their unbound fraction is fixed at one of seven values (0.05-1.0). Results span the range of hepatic extraction ratios. We achieve the cross-system validation target in 15 cases. In the other 13 cases, explanations of the in vitro-in vivo differences in disposition and removal trace to differences in compound-hepatocyte access within the two analogs during execution. The hepato-mimetic structural organization of hepatocytes within the in vivo analog, which is absent within the in vitro analog, is the determining factor. The results taken together support the feasibility of using the three-protocol plan to help explain observed in vitro-in vivo extrapolation discrepancies. We conjecture that, for some cases, the model mechanism-based explanations of discrepancies described herein will have wet-lab counterparts.

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Krishnan, P., Smith, A. K., Ropella, G. E. P., Dutta, L., Kennedy, R. C., Hunt, C. A.. 2020-10-10. Virtual experiments provide plausible explanations for IVIVE underpredictions of hepatic clearance. https://doi.org/10.1101/2020.10.09.332460

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