In Vitro–In Vivo Extrapolation of OATP1B-Mediated Drug–Drug Interactions in Cynomolgus Monkey

Abstract

Hepatic organic anion-transporting polypeptides (OATP) 1B1 and 1B3 are clinically relevant transporters associated with significant drug-drug interactions (DDIs) and safety concerns. Given that OATP1Bs in cynomolgus monkey share >90% degree of gene and amino acid sequence homology with human orthologs, we evaluated the in vitro-in vivo translation of OATP1B-mediated DDI risk using this preclinical model. In vitro studies using plated cynomolgus monkey hepatocytes showed active uptake K values of 2.0 and 3.9 M for OATP1B probe substrates, pitavastatin and rosuvastatin, respectively. Rifampicin inhibited pitavastatin and rosuvastatin active uptake in monkey hepatocytes with IC values of 3.0 and 0.54 M, respectively, following preincubation with the inhibitor. Intravenous pharmacokinetics ofH-pitavastatin and H-rosuvastatin (0.2 mg/kg) and the oral pharmacokinetics of cold probes (2 mg/kg) were studied in cynomolgus monkeys ( = 4) without or with coadministration of single oral ascending doses of rifampicin (1, 3, 10, and 30 mg/kg). A rifampicin dose-dependent reduction in i.v. clearance of statins was observed. Additionally, oral pitavastatin and rosuvastatin plasma exposure increased up to 19- and 15-fold at the highest dose of rifampicin, respectively. Use of in vitro IC obtained following 1 hour preincubation with rifampicin (0.54 M) predicted correctly the change in mean i.v. clearance and oral exposure of statins as a function of mean unbound maximum plasma concentration of rifampicin. This study demonstrates quantitative translation of in vitro OATP1B IC to predict DDIs using cynomolgus monkey as a preclinical model and provides further confidence in application of in vitro hepatocyte data for the prediction of clinical OATP1B-mediated DDIs.

Simultaneous Assessment of Transporter-Mediated Drug–Drug Interactions Using a Probe Drug Cocktail in Cynomolgus Monkey

“…All procedures performed on these animals were in accordance with regulations and established guidelines, were reviewed and approved by Pfizer Institutional Animal Care and Use Committee, and were conducted at Pfizer (Groton, CT). Male cynomolgus macaque Mauritian monkeys (6-9 years of age) were used, and the procedures similar to those previously reported were adopted with some modifications (Varma et al, 2017b;de Bruyn et al, 2018;Ufuk et al, 2018). A crossover study design was employed, in which the same four animals were dosed over all studies, following a minimum 1-week washout period between each study.…”

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

“…Therefore, an analogous approach was applied here to two widely used preclinical species, beagle dog and Sprague-Dawley rat. As a nonrodent preclinical species, beagle dogs are often used in pharmacokinetic studies; however, there is less information available to assess the predictive performance of hepatic transportermediated clearance and DDIs in this species compared with studies reported in cynomolgus monkeys (Shen et al, 2013;Chu et al, 2015;Watanabe et al, 2015;Ufuk et al, 2018). Therefore, characteristics of the hepatic uptake of a series of nine drugs were investigated to provide a data set of parameters for comparative purposes and evaluate beagle dogs as a preclinical animal model to study hepatic uptake.…”

“…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).…”

Functional characterization for polymorphic organic anion transporting polypeptides (OATP/SLCO1B1, 1B3, 2B1) of monkeys recombinantly expressed with various OATP probes

“…OATP1B1, OATP1B3 and OATP2B1 are also expressed in the liver of cynomolgus monkeys, in a manner similar to humans (Hirano, Maeda, Shitara, & Sugiyama, 2006;Takahashi et al, 2013). To predict clinical drug interactions mediated by hepatic OATPs, cynomolgus monkey models have also been proposed (Shen et al, 2013;Takahashi et al, 2013;Ufuk et al, 2018;Watanabe, Watanabe, Yabuki, & Tamai, 2015). Substrate recognition for human OATP1B1, OATP1B3 and OATP2B1 has been extensively reported and is summarized in Table 1.…”