Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, United Kingdom (A.U., J.B.H., A.G.); and Pharmacokinetics, Dynamics, and Metabolism (R.E.K., H.G., Y.-A.B., A.D.R., L.M.T., M.V.S.V.) and Research Formulations, Pharmaceutical Sciences (S.M., D.G.), Medicine Design, Pfizer Worldwide R&D, Groton, Connecticut.
Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, United Kingdom (A.U., J.B.H., A.G.); and Pharmacokinetics, Dynamics, and Metabolism (R.E.K., H.G., Y.-A.B., A.D.R., L.M.T., M.V.S.V.) and Research Formulations, Pharmaceutical Sciences (S.M., D.G.), Medicine Design, Pfizer Worldwide R&D, Groton, Connecticut
J Pharmacol Exp Ther. 2018 Jun;365(3):688-699. doi: 10.1124/jpet.118.247767. Epub 2018 Apr 11.
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 of H-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.
肝脏有机阴离子转运多肽（OATP）1B1 和 1B3 是与显著药物相互作用（DDI）和安全性问题相关的临床相关转运体。鉴于食蟹猴中的 OATP1B 在基因和氨基酸序列同源性方面与人类同源物>90%，我们使用这种临床前模型评估了 OATP1B 介导的 DDI 风险的体外-体内翻译。使用贴壁食蟹猴肝细胞进行的体外研究表明，OATP1B 探针底物匹伐他汀和罗苏伐他汀的主动摄取 K 值分别为 2.0 和 3.9 M。利福平在与抑制剂预孵育后，以分别为 3.0 和 0.54 M 的 IC 值抑制了匹伐他汀和罗苏伐他汀在猴肝细胞中的主动摄取。在未给予或给予单口服递增剂量利福平（1、3、10 和 30 mg/kg）的情况下，在食蟹猴（n = 4）中研究了 H-匹伐他汀和 H-罗苏伐他汀（0.2 mg/kg）的静脉药代动力学和冷探针（2 mg/kg）的口服药代动力学。观察到他汀类药物静脉清除率随利福平剂量呈依赖性降低。此外，在利福平的最高剂量下，口服匹伐他汀和罗苏伐他汀的血浆暴露分别增加了 19 倍和 15 倍。使用利福平（0.54 M）孵育 1 小时后获得的体外 IC 正确预测了作为利福平平均未结合最大血浆浓度函数的平均静脉清除率和他汀类药物口服暴露的变化。这项研究表明，使用食蟹猴作为临床前模型，定量转化了体外 OATP1B IC 以预测 DDI，并进一步增强了应用体外肝细胞数据预测临床 OATP1B 介导的 DDI 的信心。
