PDF(Pubmed)
Abstract：
Nirmatrelvir is a potent and selective inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease that is used as an oral antiviral coronavirus disease 2019 (COVID-19) treatment. To sustain unbound systemic trough concentrations above the antiviral in vitro 90% effective concentration value (EC90), nirmatrelvir is coadministered with 100 mg of ritonavir, a pharmacokinetic enhancer. Ritonavir inhibits nirmatrelvir\'s cytochrome P450 (CYP) 3A4-mediated metabolism which results in renal elimination becoming the primary route of nirmatrelvir elimination when dosed concomitantly. Nirmatrelvir exhibits absorption-limited nonlinear pharmacokinetics. When coadministered with ritonavir in patients with mild-to-moderate COVID-19, nirmatrelvir reaches a maximum concentration of 3.43 µg/mL (11.7× EC90) in approximately 3 h on day 5 of dosing, with a geometric mean day 5 trough concentration of 1.57 µg/mL (5.4× EC90). Drug interactions with nirmatrelvir/ritonavir (PAXLOVIDTM) are primarily attributed to ritonavir-mediated CYP3A4 inhibition, and to a lesser extent CYP2D6 and P-glycoprotein inhibition. Population pharmacokinetics and quantitative systems pharmacology modeling support twice daily dosing of 300 mg/100 mg nirmatrelvir/ritonavir for 5 days, with a reduced 150 mg/100 mg dose for patients with moderate renal impairment. Rapid clinical development of nirmatrelvir/ritonavir in response to the emerging COVID-19 pandemic was enabled by innovations in clinical pharmacology research, including an adaptive phase 1 trial design allowing direct to pivotal phase 3 development, fluorine nuclear magnetic resonance spectroscopy to delineate absorption, distribution, metabolism, and excretion profiles, and innovative applications of model-informed drug development to accelerate development.
摘要：
Nirmatrelvir是严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）主要蛋白酶的有效和选择性抑制剂，用作口服抗病毒冠状病毒病2019（COVID-19）治疗。为了维持未结合的全身谷浓度高于抗病毒体外90%有效浓度值（EC90），nirmatrelvir与100毫克的利托那韦共同给药，药代动力学增强剂。利托那韦抑制尼马特雷韦的细胞色素P450（CYP）3A4介导的代谢，当同时给药时，肾脏消除成为尼马特雷韦消除的主要途径。Nirmatrelvir表现出吸收受限的非线性药代动力学。在轻度至中度COVID-19患者中与利托那韦同时给药时，尼马特雷韦在给药第5天大约3小时内达到最大浓度3.43µg/mL（11.7×EC90），几何平均第5天波谷浓度为1.57µg/mL（5.4×EC90）。与尼马特雷韦/利托那韦（PAXLOVIDTM）的药物相互作用主要归因于利托那韦介导的CYP3A4抑制，以及较小程度的CYP2D6和P-糖蛋白抑制。群体药代动力学和定量系统药理学建模支持每天两次服用300mg/100mg尼马特雷韦/利托那韦，持续5天，对于中度肾功能损害的患者，剂量为150mg/100mg。针对新出现的COVID-19大流行，尼马特雷韦/利托那韦的快速临床发展得益于临床药理学研究的创新，包括自适应阶段1试验设计，允许直接关键阶段3开发，氟核磁共振波谱来描绘吸收，分布，新陈代谢，和排泄曲线，和模式知情药物开发的创新应用，以加速开发。
