Hepatocyte Organization Affects the Translation of Clearance from In Vitro to In Vivo

9 pages•Published: March 11, 2020

Lopamudra Dutta, Preethi Krishnan, Andrew Smith, Ryan Kennedy, Glen Ropella and C. Anthony Hunt

Abstract

An improved understanding of in vivo ⇔ in vitro changes is crucial in identifying and mitigating factors contributing to in vitro–in vivo extrapolation (IVIVE) inaccuracies in predicting the hepatic clearance of substances. We argue that a model mechanism-based virtual culture (vCulture) ⇔ virtual mouse (vMouse) (or vRat or vHuman) experiment approach can identify factors contributing to IVIVE disconnects. Doing so depends on having evidence that six Translational Requirements have been achieved. We cite evidence that the first four have been achieved. The fifth Requirement is that differences in measures of vCompound disposition between vCulture and vMouse are attributable solely to the micro-architectural, physiomimetic features, and uncertainties built into the vLiver and vMouse but are absent from the vCulture. The objective of this work is to first improve on a vCulture architecture used previously and then use results of virtual experiments to verify that its use enables the fifth Translational Requirement to be achieved. We employ two different idealized vCompounds, which map to highly permeable real compounds at the extreme ends of the intrinsic clearance spectrum. Virtual intrinsic clearance = Exposure rate per vHPC. At quasi-steady state, results for vCompound-1 are independent of the dosing rate. The average per-vHPC Exposure rates (taken over the whole vLiver in vMouse experiments) are the same (within the variance of the Experiments) as those in vCulture. However, they are location dependent within the vLiver. For vCompound-2, there are dosing rate differences and average per-vHPC Exposure rates within the vLiver are also location dependent. When we account for dosing rate differences, we see again that average per-vHPC Exposure rates averaged over the whole vLiver in vMouse experiments are the same as those in vCulture. Thus, the differences in per vHPC Exposure rate within the vLiver for both vCompounds are attributable solely to the micro-architectural and physiomimetic features built into the vLiver and vMouse but are absent from the vCulture. The results verify that the fifth Translational Requirement has been achieved.

Keyphrases: agent based, cellular exposure, hepatic clearance, in silico, in vitro in vivo extrapolation, pharmacokinetics, simulation

In: Qin Ding, Oliver Eulenstein and Hisham Al-Mubaid (editors). Proceedings of the 12th International Conference on Bioinformatics and Computational Biology, vol 70, pages 217-225.

Links:	https://easychair.org/publications/paper/wn8T
	https://doi.org/10.29007/t4kv

BibTeX entry

@inproceedings{BICOB2020:Hepatocyte_Organization_Affects_Translation,
  author    = {Lopamudra Dutta and Preethi Krishnan and Andrew Smith and Ryan Kennedy and Glen Ropella and C. Anthony Hunt},
  title     = {Hepatocyte Organization Affects the Translation of Clearance from In Vitro to In Vivo},
  booktitle = {Proceedings of the 12th International Conference on Bioinformatics and Computational Biology},
  editor    = {Qin Ding and Oliver Eulenstein and Hisham Al-Mubaid},
  series    = {EPiC Series in Computing},
  volume    = {70},
  publisher = {EasyChair},
  bibsource = {EasyChair, https://easychair.org},
  issn      = {2398-7340},
  url       = {/publications/paper/wn8T},
  doi       = {10.29007/t4kv},
  pages     = {217-225},
  year      = {2020}}

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