Predicting Human Clearance of Organic Anion Transporting Polypeptide Substrates Using Cynomolgus Monkey: In Vitro–In Vivo Scaling of Hepatic Uptake Clearance

Abstract

This work explores the utility of the cynomolgus monkey as a preclinical model to predict hepatic uptake clearance mediated by organic anion transporting polypeptide (OATP) transporters. Nine OATP substrates (rosuvastatin, pravastatin, repaglinide, fexofenadine, cerivastatin, telmisartan, pitavastatin, bosentan, and valsartan) were investigated in plated cynomolgus monkey and human hepatocytes. Total uptake clearance and passive diffusion were measured in vitro from initial rates in the absence and presence of the OATP inhibitor rifamycin SV , respectively. Total uptake clearance values in plated hepatocytes ranged over three orders of magnitude in both species, with a similar rank order and good agreement in the relative contribution of active transport to total uptake between cynomolgus monkey and human. In vivo hepatic clearance for these nine drugs was determined in cynomolgus monkey after intravenous dosing. Hepatic clearances showed a range similar to human parameters and good predictions from respective hepatocyte parameters (with 2.7- and 3.8-fold bias on average, respectively). The use of cross-species empirical scaling factors (determined from cynomolgus monkey data either as the data set average or individual drug values) improved prediction (less bias, better concordance) of human hepatic clearance from human hepatocyte data alone. In vitro intracellular binding in hepatocytes also correlated well between species. It is concluded that the minimal species differences observed for the current data set between cynomolgus monkey and human hepatocyte uptake, both in vitro and in vivo, support future use of this preclinical model to delineate drug hepatic uptake and enable prediction of human in vivo intrinsic hepatic clearance.

Positron Emission Tomography Imaging of [11C]Rosuvastatin Hepatic Concentrations and Hepatobiliary Transport in Humans in the Absence and Presence of Cyclosporin A

“…However, except for hepatocytes, primary cells from other tissues (e.g., blood–brain barrier and kidney epithelial proximal tubule cells) are either not routinely available or validated. Moreover, even where available (e.g., hepatocytes), they may not be predictive of the in vivo CL of the drug of interest . The reason for this lack of prediction is not well known but could be that the abundance and/or activity of the transporters in the cells may not represent that in vivo .…”

“…Moreover, even where available (e.g., hepatocytes), they may not be predictive of the in vivo CL of the drug of interest. [8][9][10] The reason for this lack of prediction is not well known but could be that the abundance and/or activity of the transporters in the cells may not represent that in vivo. 9 Although the relative activity factor approach can be used to surmount this shortcoming, it requires that in vivo data on tissue CL (influx and efflux) be available for the probe substrate.…”

Hepatic Organic Anion Transporting Polypeptide–Mediated Clearance in the Beagle Dog: Assessing In Vitro–In Vivo Relationships and Applying Cross-Species Empirical Scaling Factors to Improve Prediction of Human Clearance

“…The value of in vitro-derived transporter kinetic data within a physiologically based pharmacokinetic (PBPK) paradigm is now widely appreciated (Jones et al, 2015;Galetin et al, 2017;Yoshida et al, 2017;Guo et al, 2018), yet prediction success is still limited. Robust studies using preclinical animals to increase confidence in the subsequent application of in vitroin vivo extrapolation (IVIVE) of human in vitro transporter data (De Bruyn et al, 2018) would help alleviate this shortcoming.…”

“…Recently, we demonstrated the utility of the cynomolgus monkey as a preclinical species for evaluation of organic anion transporting polypeptide (OATP)-mediated hepatic clearance and DDIs (De Bruyn et al, 2018;Ufuk et al, 2018). Despite an overall good relationship between in vitro-derived clearance in cynomolgus monkey hepatocytes and in vivo clearance in the same species, the underprediction trend was apparent.…”

“…An increasing number of studies have recently investigated hepatic uptake transporter-mediated clearance and DDIs in cynomolgus monkeys, both in vitro and in vivo (Shen et al, 2013;Chu et al, 2015;De Bruyn et al, 2018;Ufuk et al, 2018). In contrast, there is minimal information on or systematic evaluation of activity of hepatic transporters in beagle dogs (Wilby et al, 2011).…”