30 covalent drugs were used to assess clearance (CL) prediction reliability in animals and humans. In animals, marked CL underprediction was observed using cryopreserved hepatocytes or liver microsomes (LMs) supplemented for cytochrome P450 activity. Improved quantitative performance was observed by combining metabolic stability data from LMs and liver S9 fractions, the latter supplemented with reduced glutathione for glutathione transferase activity. While human LMs provided reliable human CL predictions, prediction statistics were improved further by incorporating S9 stability data. CL predictions with allometric scaling were less robust compared to in vitro drug metabolism methods; the best results were obtained using the fu-corrected intercept model. Human volume of distribution (V_d) was well predicted using allometric scaling of animal pharmacokinetic data; the most reliable results were achieved using simple allometric scaling of unbound V_d values. These results provide a quantitative framework to guide appropriate method selection for human PK prediction with covalent drugs.

中文翻译：

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预测动物和人类共价药物的静脉药代动力学


使用 30 种共价药物来评估动物和人类清除率 (CL) 预测的可靠性。在动物中，使用补充细胞色素 P450 活性的冷冻保存肝细胞或肝微粒体 (LM) 观察到明显的 CL 预测不足。通过结合来自 LM 和肝脏 S9 级分的代谢稳定性数据，观察到定量性能的改善，后者补充了还原型谷胱甘肽以提高谷胱甘肽转移酶活性。虽然人类 LM 提供了可靠的人类 CL 预测，但通过合并 S9 稳定性数据，预测统计数据得到了进一步改进。与体外药物代谢方法相比，异速生长缩放的 CL 预测不太稳健；使用 fu 校正截距模型获得了最佳结果。使用动物药代动力学数据的异速生长缩放可以很好地预测人体分布容积 (V _d )；最可靠的结果是使用未结合的 V _d 值的简单异速生长缩放获得的。这些结果提供了一个定量框架来指导共价药物的人类 PK 预测的适当方法选择。