In Vitro Assessment of Potential for CYP-Inhibition-Based Drug-Drug Interaction Between Vonoprazan and Clopidogrel
In Vitro Assessment of Potential for CYP-Inhibition-Based Drug-Drug Interaction Between Vonoprazan and Clopidogrel
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DOI：
10.1007/s13318-018-0521-7
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发表时间：
2019-04-01
影响因子：
1.9
通讯作者：
Jenkins, Helen
中科院分区：
文献类型：
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作者：
Nishihara, Mitsuhiro;Yamasaki, Hitomi;Jenkins, Helen
背景和目的最近提出，CYP 介导的沃诺拉赞与氯吡格雷和普拉格雷的药物相互作用（DDI）可以减弱后两种药物的抗血小板作用。氯吡格雷通过多种 CYP（包括 CYP2C19 和 CYP3A4）代谢为具有药理活性的代谢物 H4 及其异构体。因此，为了研究基于 CYP 的 DDI 的可能性，本工作使用 CYP 探针底物或放射性标记的氯吡格雷和人肝微粒体 (HLM) 进行了体外代谢抑制研究。方法在使用或不使用 HLM 预孵育的情况下，进行了可逆抑制研究，重点关注沃诺拉赞对 CYP 标记物活性和 [C-14]氯吡格雷代谢物 H4 形成的影响。还测量了时间依赖性抑制 (TDI) 动力学。 结果发现，vonoprazan 不是任何 CYP 异构体 (IC(50)16M) 的显着直接抑制剂，但显示出 CYP2B6、CYP2C19 和 CYP3A4/5 的 TDI 潜力。根据测量的效力（k（无活性）/K-I 比率和 R2 值），该 TDI 弱于相应参考抑制剂噻氯匹定、埃索美拉唑和维拉帕米诱导的抑制作用。在一项更直接的体外实验中，沃诺拉赞浓度高达 10 muM（比每天服用 20mg 连续 7 天后血浆 C-max 75.9nM 高 100 倍）并不会以可逆或时间依赖性方式抑制[C-14]氯吡格雷活性代谢物 H4 或其他氧化代谢物的形成。此外，对临床试验和上市后数据的评估表明，没有证据表明沃诺拉赞和氯吡格雷之间存在 DDI。 结论 大量证据表明，沃诺拉赞和氯吡格雷之间报道的药效学 DDI 不太可能是由沃诺拉赞抑制 CYP2B6、CYP2C19 或 CYP3A4/5 引起的。
Background and ObjectivesIt was recently proposed that CYP-mediated drug-drug interactions (DDIs) of vonoprazan with clopidogrel and prasugrel can attenuate the antiplatelet actions of the latter two drugs. Clopidogrel is metabolized to the pharmacologically active metabolite H4 and its isomers by multiple CYPs, including CYP2C19 and CYP3A4. Therefore, to investigate the possibility of CYP-based DDIs, in vitro metabolic inhibition studies using CYP probe substrates or radiolabeled clopidogrel and human liver microsomes (HLMs) were conducted in this work.MethodsReversible inhibition studies focusing on the effects of vonoprazan on CYP marker activities and the formation of the [C-14]clopidogrel metabolite H4 were conducted with and without pre-incubation using HLMs. Time-dependent inhibition (TDI) kinetics were also measured.ResultsIt was found that vonoprazan is not a significant direct inhibitor of any CYP isoforms (IC(50)16M), but shows the potential for TDI of CYP2B6, CYP2C19, and CYP3A4/5. This TDI was weaker than the inhibition induced by the corresponding reference inhibitors ticlopidine, esomeprazole, and verapamil, based on the measured potencies (k(inact)/K-I ratio and the R2 value). In a more direct in vitro experiment, vonoprazan levels of up to 10 mu M (a 100-fold higher concentration than the plasma C-max of 75.9nM after taking 20mg once daily for 7days) did not suppress the formation of the active metabolite H4 or other oxidative metabolites of [C-14]clopidogrel in a reversible or time-dependent manner. Additionally, an assessment of clinical trials and post-marketing data suggested no evidence of a DDI between vonoprazan and clopidogrel.ConclusionsThe body of evidence shows that the pharmacodynamic DDI reported between vonoprazan and clopidogrel is unlikely to be caused by the inhibition of CYP2B6, CYP2C19, or CYP3A4/5 by vonoprazan.