Bayer AG, Research and Development, Pharmaceuticals, Clinical Sciences, Wuppertal, Germany.
Bayer AG, Research and Development, Pharmaceuticals, DMPK, Wuppertal, Germany.
Eur J Drug Metab Pharmacokinet. 2020 Aug;45(4):433-444. doi: 10.1007/s13318-020-00610-y.
In vivo studies were performed with the novel, selective, non-steroidal mineralocorticoid receptor antagonist finerenone to assess the relevance of inductive and/or inhibitory effects on cytochrome P450 (CYP) enzymes observed in vitro.
CYP isoenzyme-specific substrates were incubated in vitro with finerenone or its metabolites to investigate reversible and irreversible inhibitory as well as inductive potential. Three crossover studies in healthy male volunteers investigated the effects of finerenone (20 mg orally) on the pharmacokinetics of the index substrates midazolam (CYP3A4, n = 30), repaglinide (CYP2C8, n = 28) and warfarin (CYP2C9, n = 24).
Finerenone caused direct inhibitory effects on CYP activities in vitro in the rank order CYP2C8, CYP1A1 > CYP3A4 > CYP2C9 and CYP2C19, but not on other major CYP isoforms. Moreover, irreversible inhibition of CYP3A4 was observed. The major metabolites of finerenone demonstrated minor reversible inhibition of CYP1A1, CYP2C9 and CYP3A4 with no hint of time-dependent inhibition of any CYP isoform. Calculations from in vitro data according to regulatory guidelines suggested likely inhibition of CYP2C8 and CYP3A4 in vivo, whereas this was not the case for CYP1A1, CYP2C9 and CYP2C19. Furthermore, finerenone and three of its metabolites were inducers of CYP3A4 in vitro with predicted weak-to-moderate in vivo relevance. Studies in healthy volunteers, prompted by these results, demonstrated no effect of finerenone on CYP isoenzymes for which in vitro data had indicated potential inhibition or induction.
Administration of finerenone 20 mg once daily confers no risk of clinically relevant drug-drug interactions with substrates of cytochrome P450 enzymes.
本研究使用新型、选择性、非甾体类盐皮质激素受体拮抗剂非奈利酮进行了体内研究，以评估体外观察到的对细胞色素 P450（CYP）酶的诱导和/或抑制作用的相关性。
将 CYP 同工酶特异性底物与非奈利酮或其代谢物在体外孵育，以研究可逆和不可逆抑制以及诱导潜力。在健康男性志愿者中进行了三项交叉研究，以研究非奈利酮（20mg 口服）对指数底物咪达唑仑（CYP3A4，n=30）、瑞格列奈（CYP2C8，n=28）和华法林（CYP2C9，n=24）的药代动力学的影响。
非奈利酮在体外对 CYP 活性具有直接抑制作用，抑制作用的等级顺序为 CYP2C8、CYP1A1>CYP3A4>CYP2C9 和 CYP2C19，但对其他主要 CYP 同工酶没有作用。此外，还观察到 CYP3A4 的不可逆抑制。非奈利酮的主要代谢物对 CYP1A1、CYP2C9 和 CYP3A4 表现出轻微的可逆抑制，没有任何 CYP 同工酶的时间依赖性抑制的迹象。根据监管指南，从体外数据计算表明，非奈利酮在体内可能抑制 CYP2C8 和 CYP3A4，但对 CYP1A1、CYP2C9 和 CYP2C19 则不然。此外，非奈利酮及其三种代谢物在体外诱导 CYP3A4，具有弱至中度的体内相关性。这些结果促使在健康志愿者中进行的研究表明，非奈利酮对体外数据表明有潜在抑制或诱导作用的 CYP 同工酶没有影响。
每天口服 20mg 非奈利酮不会导致与细胞色素 P450 酶底物发生有临床意义的药物相互作用的风险。
