Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of Remdesivir, a SARS-CoV-2 Replication Inhibitor.
Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of Remdesivir, a SARS-CoV-2 Replication Inhibitor.
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DOI：
10.1007/s40262-021-00984-5
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发表时间：
2021-05
影响因子：
4.5
通讯作者：
German P
中科院分区：
文献类型：
--
作者：
Humeniuk R;Mathias A;Kirby BJ;Lutz JD;Cao H;Osinusi A;Babusis D;Porter D;Wei X;Ling J;Reddy YS;German P
Remdesivir（RDV，Veklury®）是一种每日一次的核苷核糖核酸聚合酶抑制剂，可抑制严重急性呼吸综合征冠状病毒2型的复制。Remdesivir已在多个国家获批用于因2019年严重冠状病毒病（COVID-19）住院的成人和儿童。在细胞内，Remdesivir经历代谢活化以形成细胞内活性三磷酸代谢物GS-443902（在外周血单核细胞中检测到），并最终形成经肾脏消除的血浆代谢物GS-441524。本综述讨论了RDV的临床前药理学、临床药代动力学、药效学/浓度-QT分析、COVID-19患者治疗剂量选择的基本原理以及基于健康志愿者的体外和临床数据的药物相互作用潜力。在健康受试者中，在3-225 mg剂量范围内单次静脉给予RDV溶液制剂2小时后，RDV及其代谢产物（GS-704277和GS-441524）表现出线性药代动力学。RDV 150 mg每日一次多次给药7或14天后，主要代谢产物GS-441524在血浆中蓄积约1.9倍。基于动物数据和健康志愿者中可用的人体数据的药代动力学桥接，选择第1天200 mg负荷剂量，随后100 mg维持剂量4天或9天的RDV临床给药方案用于进一步评价药代动力学和安全性。结果显示GS-443902的高细胞内浓度表明从RDV有效转化为三磷酸形式，并进一步支持用于治疗COVID-19的这种临床给药方案。基于体外和I期数据的数学药物相互作用倾向预测表明，RDV发生药物相互作用的可能性较低，因为诱导剂或抑制剂对RDV处置的影响通过胃肠外给药途径和广泛提取降至最低。使用基于生理学的药代动力学模型，预计RDV在治疗剂量下不会成为COVID-19感染患者中药物代谢酶或转运蛋白的临床显著抑制剂。在线版本包含补充材料，可通过10.1007/s40262-021-00984-5获得。
Remdesivir (RDV, Veklury®) is a once-daily, nucleoside ribonucleic acid polymerase inhibitor of severe acute respiratory syndrome coronavirus 2 replication. Remdesivir has been granted approvals in several countries for use in adults and children hospitalized with severe coronavirus disease 2019 (COVID-19). Inside the cell, remdesivir undergoes metabolic activation to form the intracellular active triphosphate metabolite, GS-443902 (detected in peripheral blood mononuclear cells), and ultimately, the renally eliminated plasma metabolite GS-441524. This review discusses the pre-clinical pharmacology of RDV, clinical pharmacokinetics, pharmacodynamics/concentration-QT analysis, rationale for dose selection for treatment of patients with COVID-19, and drug–drug interaction potential based on available in vitro and clinical data in healthy volunteers. Following single-dose intravenous administration over 2 h of an RDV solution formulation across the dose range of 3–225 mg in healthy participants, RDV and its metabolites (GS-704277and GS-441524) exhibit linear pharmacokinetics. Following multiple doses of RDV 150 mg once daily for 7 or 14 days, major metabolite GS-441524 accumulates approximately 1.9-fold in plasma. Based on pharmacokinetic bridging from animal data and available human data in healthy volunteers, the RDV clinical dose regimen of a 200-mg loading dose on day 1 followed by 100-mg maintenance doses for 4 or 9 days was selected for further evaluation of pharmacokinetics and safety. Results showed high intracellular concentrations of GS-443902 suggestive of efficient conversion from RDV into the triphosphate form, and further supporting this clinical dosing regimen for the treatment of COVID-19. Mathematical drug–drug interaction liability predictions, based on in vitro and phase I data, suggest RDV has low potential for drug–drug interactions, as the impact of inducers or inhibitors on RDV disposition is minimized by the parenteral route of administration and extensive extraction. Using physiologically based pharmacokinetic modeling, RDV is not predicted to be a clinically significant inhibitor of drug-metabolizing enzymes or transporters in patients infected with COVID-19 at therapeutic RDV doses. The online version contains supplementary material available at 10.1007/s40262-021-00984-5.
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影响因子：
2.9
作者：
Mohamed, Mohamed-Eslam F.;Rakhmanina, Natella;Hassan, Hazem E.
通讯作者：
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Spiropoulou CF
影响因子：
158.5
作者：
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通讯作者：
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