Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-in vivo predictions of hepatic clearance

Abstract

We demonstrate how results of virtual experiments can suggest mechanism-based explanations for IVIVE underpredictions of hepatic clearance. We use agent-oriented, discrete-event methods. We experiment on software analogies of rats and hepatocyte cultures dosed identically with objects that mimic two idealized compounds, vC1 (not cleared) and vC2 (removal maximized). Hepatocytes in cultures and rat livers interact identically with vC1 and vC2. The rules governing vC1 and vC2 movements and interactions with hepatocytes are the same in both systems. The two software systems are independent; to be useful in discovering plausible explanations of IVIVE inaccuracies, we require that, in the absence of hepatocyte exposure differences, the culture-to-rat scaling factor = 1.0 for all corresponding measures. The probability of cell entry (pEnter) maps directly to the unbound-fraction of drug used by IVIVE methods. For vC1 (vC2), we achieve that validation target for pEnter = 0.05-1.0 (1.0). However, for pEnter = 0.05-0.8, vC2 removal rates during culture experiments underpredicted corresponding removal rates in rats. The magnitude of the underpredictions increases with decreasing pEnter. For example, using pEnter = 0.1 (0.3), peak vC2 removal rates in culture experiments underpredict corresponding removal rates in rats by 3.2 (1.4) fold. Underpredictions are a consequence of the biomimetic periportal-to-pericentral organization of hepatocytes within virtual livers are absent in virtual cultures. In rats, pericentral hepatocytes do more of the vC2 removal work. The results suggest that using IVIVE methods that abstract away influential features of hepatocyte organization within livers may contribute to IVIVE underpredictions.Significance StatementFrom experiments on virtual (software) counterparts of rats and hepatocyte cultures, we learned that IVIVE underpredictions are a consequence of the biomimetic periportal-to-pericentral organization of hepatocytes within virtual livers being absent in virtual cultures. Using IVIVE methods that abstract away influential features of hepatocyte organization within livers may contribute in part to some IVIVE underpredictions.Visual Abstract