Pitavastatin as an In Vivo Probe for Studying Hepatic Organic Anion Transporting Polypeptide-Mediated Drug–Drug Interactions in Cynomolgus Monkeys

Abstract

Drug-drug interactions (DDIs) caused by the inhibition of hepatic uptake transporters such as organic anion transporting polypeptide (OATP) can affect therapeutic efficacy and cause adverse reactions. We investigated the potential utility of pitavastatin as an in vivo probe substrate for preclinically studying OATP-mediated DDIs using cynomolgus monkeys. Cyclosporine A (CsA) and rifampicin (RIF), typical OATP inhibitors, inhibited active uptake of pitavastatin into monkey hepatocytes with half-maximal inhibitory concentration values comparable with those in human hepatocytes. CsA and RIF increased the area under the plasma concentration-time curve (AUC) of intravenously administered pitavastatin in cynomolgus monkeys by 3.2-and 3.6-fold, respectively. In addition, there was no apparent prolongation of the elimination half-life of pitavastatin due to the decrease in both hepatic clearance and volume of distribution. These findings suggest that DDIs were caused by the inhibition of hepatic uptake of pitavastatin. CsA and RIF increased the AUC of orally administered pitavastatin by 10.6-and 14.8-fold, respectively, which was additionally caused by the effect of the CsA and RIF in the gastrointestinal tract. Hepatic contribution to the overall DDI for oral pitavastatin with CsA was calculated from the changes in hepatic availability and clearance, and it was shown that the magnitude of hepatic DDI was comparable between the present study and the clinical study. In conclusion, pharmacokinetic studies using pitavastatin as a probe in combination with drug candidates in cynomolgus monkeys are useful to support the assessment of potential clinical DDIs involving hepatic uptake transporters.

Cynomolgus Monkey as a Clinically Relevant Model to Study Transport Involving Renal Organic Cation Transporters: In Vitro and In Vivo Evaluation

“…Recently, an increasing number of investigators have used the cynomolgus monkey as a model to study the inhibition of drug transporters in vivo (Tahara et al, 2006;Shen et al, 2013Shen et al, , 2015bTakahashi et al, 2013;Uchida et al, 2014;Chu et al, 2015;Karibe et al, 2015). Such a model offers advantages in drug development, when the transporter inhibition potential of a clinical candidate requires more extensive evaluation of changes in victim drug pharmacokinetics and organ toxicity.…”

Evaluation of Cynomolgus Monkeys for the Identification of Endogenous Biomarkers for Hepatic Transporter Inhibition and as a Translatable Model to Predict Pharmacokinetic Interactions with Statins in Humans

“…Both cOATP1B1 and cOATP1B3 are functionally similar to their human orthologs, both in terms of in vitro transport activity and inhibition potency with selected substrates and inhibitors tested (Shen et al, 2013). Importantly, in vivo DDIs of rosuvastatin (RSV) and pitavastatin with rifampin (RIF), a potent inhibitor of OATP1B, have been reported in cynomolgus monkeys (Shen et al, 2013;Takahashi et al, 2013). It is therefore conceivable that cynomolgus monkeys could be an appropriate preclinical model to identify endogenous biomarkers that are also sensitive to OATP1B inhibition in humans.…”

“…and PO administration of the statins tested, respectively, to ensure that the RIF concentrations reached a maximum level at early time points after i.v. and PO dosing of RSV or ATV (Shen et al, 2013;Takahashi et al, 2013). The animals were divided into various treatment groups with four animals in each group: RIF PO, RSV or ATV i.v., RSV or ATV PO, RSV or ATV i.v.…”

Evaluation of Rosuvastatin as an Organic Anion Transporting Polypeptide (OATP) Probe Substrate: In Vitro Transport and In Vivo Disposition in Cynomolgus Monkeys

“…It has been reported that cynomolgus monkey OATPs (cOATPs) share a high degree of amino acid sequence identity and functional similarity to their human counterparts (Shen et al, 2013;Takahashi et al, 2013). Concomitant with these identities and similarities, there are investigations employing the cynomolgus monkey as an in vivo preclinical model to assess OATP DDIs (Shen et al, 2013;Takahashi et al, 2013).…”

“…Concomitant with these identities and similarities, there are investigations employing the cynomolgus monkey as an in vivo preclinical model to assess OATP DDIs (Shen et al, 2013;Takahashi et al, 2013). The DDIs have been investigated in other animal models; however, the sequences and transporting profiles obtained for xenobiotics in other animal species are frequently different from those obtained in humans, reducing the utility of such animals (Shitara et al, 2003;Shirasaka et al, 2010;Li et al, 2013).…”