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

Abstract

Inhibition of hepatic transporters such as organic anion transporting polypeptides (OATPs) 1B can cause drug-drug interactions (DDIs). Determining the impact of perpetrator drugs on the plasma exposure of endogenous substrates for OATP1B could be valuable to assess the risk for DDIs early in drug development. As OATP1B orthologs are well conserved between human and monkey, we assessed in cynomolgus monkeys the endogenous OATP1B substrates that are potentially suitable to assess DDI risk in humans. The effect of rifampin (RIF), a potent inhibitor for OATP1B, on plasma exposure of endogenous substrates of hepatic transporters was measured. From the 18 biomarkers tested, RIF (18 mg/kg, oral) caused significant elevation of plasma unconjugated and conjugated bilirubin, which may be attributed to inhibition of cOATP1B1 and cOATP1B3 based on in vitro to in vivo extrapolation analysis. To further evaluate whether cynomolgus monkeys are a suitable translational model to study OATP1B-mediated DDIs, we determined the inhibitory effect of RIF on in vitro transport and pharmacokinetics of rosuvastatin (RSV) and atorvastatin (ATV). RIF strongly inhibited the uptake of RSV and ATV by cOATP1B1 and cOATP1B3 in vitro. In agreement with clinical observations, RIF (18 mg/kg, oral) significantly decreased plasma clearance and increased the area under the plasma concentration curve (AUC) of intravenously administered RSV by 2.8-and 2.7-fold, and increased the AUC and maximum plasma concentration of orally administered RSV by 6-and 10.3-fold, respectively. In contrast to clinical findings, RIF did not significantly increase plasma exposure of either intravenous or orally administered ATV, indicating species differences in the rate-limiting elimination pathways.

Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition

“…OATP inhibition can cause hyperbilirubinemia (Campbell et al, 2004). Indeed, bilirubin levels are markedly increased in the plasma of cynomolgus monkeys and rats after administration of RIF (Chu et al, 2015;Watanabe et al, 2015); thus, the authors proposed bilirubin as a biomarker for hepatic OATP inhibition. However, in addition to the biochemical defect leading to reduced hepatic uptake of conjugated and unconjugated bilirubin, other factors, such as impaired efflux transporters (MRP2 and MRP3) and enzyme activity (UGT1A1), may also result in changes in bilirubin plasma concentration.…”

“…Total, Direct, and Indirect Bilirubin in Human Plasma. As indirect bilirubin is a substrate of OATP transporters and increases in plasma bilirubin in cynomolgus monkeys and rats after RIF administration have been reported (Chu et al, 2015), we further examined total, direct, and indirect bilirubin in plasma of human subjects receiving RSV alone (period 1) or the combination of RIF and RSV (period 3). As shown in Fig.…”

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.…”

Coproporphyrins I and III as Functional Markers of OATP1B Activity: In Vitro and In Vivo Evaluation in Preclinical Species

“…1, A and B). OATP1B involvement in the transport of CP was further confirmed by inhibition of the uptake by coincubation of the cells with 100 mM RIF, a potent inhibitor of each of these OATP transporters (Shen et al, 2013, Chu et al, 2015. The validity of the OATP assays was confirmed with commonly used positive controls for monkey and human OATP1B1 ([ Probe substrate uptake by the HEK cells expressing OATPs were significantly enhanced compared with MOCK-HEK cells and uptakes were greatly inhibited by 100 mM RIF, which confirmed the functional activity in cellular uptake of OATP substrates.…”

“…Bilirubin and bile acids are proposed to be biomarkers for hepatic OATP inhibition as suggested by their increased plasma levels in cynomolgus monkeys and rats after administration of RIF (Chu et al, 2015;Watanabe et al, 2015). However, in addition to the biochemical defect leading to reduced hepatic uptake of conjugated and unconjugated bilirubin, other factors such as impaired efflux transporters (MRP2 and MRP3) and enzyme activity (UGT1A1) may also result in the change in bilirubin plasma concentration.…”