Clinical Pharmacology Cardiovascular/Haematology, Translational Sciences, Research & Development, Bayer AG, Wuppertal, Germany.
Drug Metabolism and Pharmacokinetics, Translational Sciences, Research & Development, Bayer AG, Wuppertal, Germany.
Basic Clin Pharmacol Toxicol. 2021 Mar;128(3):511-524. doi: 10.1111/bcpt.13538. Epub 2020 Dec 12.
Molidustat is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl-hydroxylase enhancing the erythropoietin (EPO) response to HIF; it is in clinical development for the treatment of anaemia related to chronic kidney disease. The predominant role of glucuronidation for molidustat clearance (formation of N-glucuronide metabolite M1) and subsequent renal excretion was confirmed in a human mass balance study, with about 85% of the drug being excreted as M1 in urine. The inhibitory effects of 176 drugs and xenobiotics from various compound classes on the UGT-mediated glucuronidation of molidustat in human liver microsomes (HLMs) were investigated. Based on preclinical findings, glucuronidation of molidustat was predominantly mediated by the 5'-diphospho-glucuronosyltransferase (UGT) isoform UGT1A1. Therefore, atazanavir, which is a potent inhibitor of UGT1A1, was chosen for the evaluation of pharmacokinetics and EPO release following a single oral dose of 25 mg molidustat. Molidustat exposure increased about twofold upon coadministration with atazanavir when considering area under plasma concentration-time curve from zero to infinity (AUC) and maximum plasma concentration (C ). Baseline-corrected increase of EPO was 14% and 34% for C and AUC (calculated over 24 hours), respectively. Coadministration of molidustat and atazanavir was well tolerated.
莫利司他是一种缺氧诱导因子（HIF）脯氨酰羟化酶的口服抑制剂，可增强促红细胞生成素（EPO）对 HIF 的反应；它正在开发用于治疗与慢性肾病相关的贫血。在一项人体质量平衡研究中证实，莫利司他的清除（形成 N-葡萄糖醛酸化物 M1）和随后的肾脏排泄主要通过葡萄糖醛酸化，约 85%的药物以 M1 的形式从尿液中排泄。研究了来自各种化合物类别的 176 种药物和外源性物质对人肝微粒体（HLM）中莫利司他 UGT 介导的葡萄糖醛酸化的抑制作用。基于临床前发现，莫利司他的葡萄糖醛酸化主要由 5'-二磷酸葡萄糖醛酸基转移酶（UGT）同工型 UGT1A1 介导。因此，选择阿扎那韦（一种强效 UGT1A1 抑制剂）来评估莫利司他单剂量 25mg 口服给药后的药代动力学和 EPO 释放。当考虑从零到无穷大的血浆浓度-时间曲线下面积（AUC）和最大血浆浓度（C）时，莫利司他与阿扎那韦联合用药时暴露量增加了约两倍。C 和 AUC（计算 24 小时）的 EPO 校正后基线增加分别为 14%和 34%。莫利司他和阿扎那韦联合用药的耐受性良好。
