Shibata Yoshihiro, Chiba Masato
Discovery Drug Metabolism and Pharmacokinetics, Pharmacokinetics Research Laboratories, Tsukuba Research Center, Taiho Pharmaceutical Co. Ltd., Ibaraki, Japan
Discovery Drug Metabolism and Pharmacokinetics, Pharmacokinetics Research Laboratories, Tsukuba Research Center, Taiho Pharmaceutical Co. Ltd., Ibaraki, Japan.
Drug Metab Dispos. 2015 Mar;43(3):375-84. doi: 10.1124/dmd.114.061424. Epub 2014 Dec 10.
Despite the fact that much progress has been made recently in the development of targeted covalent inhibitors (TCIs), their pharmacokinetics (PK) have not been well characterized in the light of extrahepatic clearance (CLextH) by glutathione (GSH)/glutathione S-transferase (GST)-dependent conjugation attributable to the unique electrophilic structure (e.g., acrylamide moiety) of TCI compounds. In the present study, CLextH values were examined in rat, dog, and monkey to predict the contribution of CLextH to the PK of the TCIs afatinib, ibrutinib, and neratinib in humans. Afatinib and neratinib both underwent extensive conjugation with GSH in buffer and cytosol fractions of liver and kidney, whereas ibrutinib showed much lower reactivity/susceptibility to GSH/GST-dependent conjugation. The CLextH in each species was calculated from the difference between observed total body clearance and predicted hepatic clearance (CLH) in cryopreserved hepatocytes suspended in 100% serum of the corresponding species. The power-based simple allometry relating the CLextH for the unbound compound to animal body weight was applicable across species for afatinib and neratinib (R(2) ≥ 0.9) but not for ibrutinib (R(2) = 0.04). The predicted AUC after oral administration of afatinib and neratinib agreed reasonably closely with reported values in phase I dose-escalation studies. Comparisons of CLextH and CLH predicted that CLextH largely determined the PK of afatinib (>90% as a proportion of total body clearance) and neratinib (∼34%) in humans. The present method can serve as one of the tools for the optimization of PK in humans at the discovery stage for the development of TCI candidates.
尽管靶向共价抑制剂（TCI）的研发最近取得了很大进展，但其药代动力学（PK）尚未根据谷胱甘肽（GSH）/谷胱甘肽S-转移酶（GST）依赖性结合导致的肝外清除率（CLextH）进行充分表征，这是由于TCI化合物独特的亲电结构（例如丙烯酰胺部分）所致。在本研究中，检测了大鼠、狗和猴子的CLextH值，以预测CLextH对人类中TCI阿法替尼、伊布替尼和来那替尼PK的贡献。阿法替尼和来那替尼在肝脏和肾脏的缓冲液和胞质溶胶部分均与GSH发生广泛结合，而伊布替尼对GSH/GST依赖性结合的反应性/敏感性则低得多。每个物种的CLextH是根据观察到的总体清除率与悬浮在相应物种100%血清中的冷冻保存肝细胞中预测的肝清除率（CLH）之间的差异计算得出的。将游离化合物的CLextH与动物体重相关联的基于幂的简单异速生长法适用于阿法替尼和来那替尼的跨物种研究（R(2)≥0.9），但不适用于伊布替尼（R(2)=0.04）。口服阿法替尼和来那替尼后的预测AUC与I期剂量递增研究中的报告值相当接近。CLextH和CLH的比较预测，CLextH在很大程度上决定了人类中阿法替尼（占总体清除率的比例>90%）和来那替尼（约34%）的PK。本方法可作为在TCI候选药物研发的发现阶段优化人类PK的工具之一。
