Jiang Rongrong, Hart Andrew, Burgess Laurette, Kim Dae-Shik, Lai Weidong George, Dixit Vaishali
Drug Metabolism and Pharmacokinetics (R.J., V.D., W.G.L., A.H.) and Genetics Guided Dementia Discovery, Eisai Inc, Cambridge, Massachusetts (L.B., D.-S.K.)
Drug Metabolism and Pharmacokinetics (R.J., V.D., W.G.L., A.H.) and Genetics Guided Dementia Discovery, Eisai Inc, Cambridge, Massachusetts (L.B., D.-S.K.).
Drug Metab Dispos. 2021 Mar;49(3):265-275. doi: 10.1124/dmd.120.000125. Epub 2020 Dec 18.
E7766 represents a novel class of macrocycle-bridged dinucleotides and is under clinical development for immuno-oncology. In this report, we identified mechanism of systemic clearance E7766 and investigated the hepatobiliary transporters involved in the disposition of E7766 and potential drug interactions of E7766 as a victim of organic anion-transporting polypeptide (OATP) inhibitors. In bile-duct cannulated rats and dogs, E7766 was mainly excreted unchanged in bile (>80%) and to a lesser extent in urine (<20%). Sandwich-cultured human hepatocytes (SCHHs), transfected cells, and vesicles were used to phenotype the hepatobiliary transporters involved in the clearance of E7766. SCHH data showed temperature-dependent uptake of E7766 followed by active biliary secretion. In vitro transport assays using transfected cells and membrane vesicles confirmed that E7766 was a substrate of OATP1B1, OATP1B3, and multidrug resistance-associated protein 2. Phenotyping studies suggested predominant contribution of OATP1B3 over OATP1B1 in the hepatic uptake of E7766. Studies in OATP1B1/1B3 humanized mice showed that plasma exposure of E7766 increased 4.5-fold when coadministered with Rifampicin. Physiologically based pharmacokinetic models built upon two independent bottom-up approaches predicted elevation of E7766 plasma exposure when administered with Rifampicin, a clinical OATP inhibitor. In conclusion, we demonstrate that OATP-mediated hepatic uptake is the major contributor to the clearance of E7766, and inhibition of OATP1B may increase its systemic exposure. Predominant contribution of OATP1B3 in the hepatic uptake of E7766 was observed, suggesting polymorphisms in OATP1B1 would be unlikely to cause variability in the exposure of E7766. SIGNIFICANCE STATEMENT: Understanding the clearance mechanisms of new chemical entities is critical to predicting human pharmacokinetics and drug interactions. A physiologically based pharmacokinetic model that incorporated parameters from mechanistic in vitro and in vivo experiments was used to predict pharmacokinetics and drug interactions of E7766, a novel dinucleotide drug. The findings highlighted here may shed a light on the pharmacokinetic profile and transporter-mediated drug interaction propensity of other dinucleotide drugs.
E7766代表一类新型的大环桥连二核苷酸，正在进行免疫肿瘤学的临床开发。在本报告中，我们确定了E7766的全身清除机制，并研究了参与E7766处置的肝胆转运体以及E7766作为有机阴离子转运多肽（OATP）抑制剂的受害者时的潜在药物相互作用。在胆管插管的大鼠和犬中，E7766主要以原形经胆汁排泄（>80%），经尿液排泄的比例较小（<20%）。采用三明治培养的人肝细胞（SCHH）、转染细胞和囊泡来确定参与E7766清除的肝胆转运体的表型。SCHH数据显示E7766的摄取具有温度依赖性，随后是主动胆汁分泌。使用转染细胞和膜囊泡进行的体外转运试验证实E7766是OATP1B1、OATP1B3和多药耐药相关蛋白2的底物。表型研究表明，在肝脏摄取E7766方面，OATP1B3比OATP1B1的贡献更大。在OATP1B1/1B3人源化小鼠中的研究表明，与利福平合用时，E7766的血浆暴露量增加了4.5倍。基于两种独立的自下而上方法构建的生理药代动力学模型预测，与临床OATP抑制剂利福平合用时，E7766的血浆暴露量会升高。总之，我们证明OATP介导的肝脏摄取是E7766清除的主要贡献因素，抑制OATP1B可能会增加其全身暴露量。观察到OATP1B3在肝脏摄取E7766方面的主要贡献，这表明OATP1B1中的多态性不太可能导致E7766暴露的变异性。意义声明：了解新化学实体的清除机制对于预测人体药代动力学和药物相互作用至关重要。一个结合了体外和体内机制实验参数的生理药代动力学模型被用于预测新型二核苷酸药物E7766的药代动力学和药物相互作用。此处突出的研究结果可能为其他二核苷酸药物的药代动力学特征和转运体介导的药物相互作用倾向提供线索。
