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In Vitro - in Vivo Extrapolation of Hepatic Clearance in Preclinical Species

A Correction to this article was published on 21 March 2022

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Abstract

Accurate prediction of human clearance is of critical importance in drug discovery. In this study, in vitroin vivo extrapolation (IVIVE) of hepatic clearance was established using large sets of compounds for four preclinical species (mouse, rat, dog, and non-human primate) to enable better understanding of clearance mechanisms and human translation. In vitro intrinsic clearances were obtained using pooled liver microsomes (LMs) or hepatocytes (HEPs) and scaled to hepatic clearance using the parallel-tube and well-stirred models. Subsequently, IVIVE scaling factors (SFs) were derived to best predict in vivo clearance. The SFs for extended clearance classification system (ECCS) class 2/4 compounds, involving metabolic clearance, were generally small (≤ 2.6) using both LMs and HEPs with parallel-tube model, with the exception of the rodents (~ 2.4–4.6), suggesting in vitro reagents represent in vivo reasonably well. SFs for ECCS class 1A and 1B are generally higher than class 2/4 across the species, likely due to the contribution of transporter-mediated clearance that is under-represented with in vitro reagents. The parallel-tube model offered lower variability in clearance predictions over the well-stirred model. For compounds that likely demonstrate passive permeability-limited clearance in vitro, rat LM predicted in vivo clearance more accurately than HEP. This comprehensive analysis demonstrated reliable IVIVE can be achieved using LMs and HEPs. Evaluation of clearance IVIVE in preclinical species helps to better understand clearance mechanisms, establish more reliable IVIVE in human, and enhance our confidence in human clearance and PK prediction, while considering species differences in drug metabolizing enzymes and transporters.

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Tess, D.A., Ryu, S. & Di, L. In Vitro - in Vivo Extrapolation of Hepatic Clearance in Preclinical Species. Pharm Res 39, 1615–1632 (2022). https://doi.org/10.1007/s11095-022-03205-1

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Keywords

  • clearance
  • IVIVE
  • hepatocytes
  • liver microsomes
  • passive permeability-limited clearance
  • transporters