Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir.
Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir.
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DOI：
10.1002/cpt.2603
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发表时间：
2022-07
影响因子：
6.7
通讯作者：
Bergman, Arthur
中科院分区：
文献类型：
--
作者：
Singh, Ravi Shankar P.;Toussi, Sima S.;Hackman, Frances;Chan, Phylinda L.;Rao, Rohit;Allen, Richard;Van Eyck, Lien;Pawlak, Sylvester;Kadar, Eugene P.;Clark, Frances;Shi, Haihong;Anderson, Annaliesa S.;Binks, Michael;Menon, Sandeep;Nucci, Gianluca;Bergman, Arthur
2019冠状病毒病（COVID - 19）仍然是住院和死亡的主要原因。目前迫切需要安全、有效的COVID - 19抗病毒药物。Nirmatrelvir （PF‐07321332）是首个口服生物有效的抗冠状病毒家族的严重急性呼吸综合征冠状病毒2 (SARS‐CoV‐2)Mpro抑制剂，已显示出有效的临床前抗病毒活性和良好的安全性。我们报告了一项加速随机、双盲、安慰剂对照的I期研究中，nirmatrelvir加利托那韦和不加利托那韦的安全性、耐受性和药代动力学数据。两个交叉的单次上升剂量（SAD）队列在三期交叉中进行评估。在5个平行队列中，对每日两次尼马特利韦/利托那韦的多次上升剂量（MAD）进行了10天的评估。安全性进行了评估，包括在超治疗暴露队列中。通过将SAD/MAD数据与非临床数据和定量系统药理学模型（QSP）整合建模和模拟，支持II/III期临床试验中临床疗效评估的剂量和给药方案。在SAD、MAD和超治疗暴露队列中，尼马特利韦/利托那韦是安全且耐受性良好的。利托那韦大大增加了尼马特利韦的暴露量和半衰期，使尼马特利韦/利托那韦的剂量和方案能够在II/III期试验中选择（300/ 100mg b.i.d），使浓度持续高于体外抑制90%病毒复制所需的浓度。QSP模型提示，5天的治疗方案可以显著降低SARS - CoV - 2感染患者的病毒载量，从而可能预防严重疾病的发展、住院和死亡。总之，创新和无缝的试验设计加速了nirmatrelvir/ritonavir I期安全性和药代动力学的建立，使II/III期剂量选择具有高可信度，并加速了关键试验的启动（NCT04756531）。
Coronavirus disease 2019 (COVID‐19) is a continued leading cause of hospitalization and death. Safe, efficacious COVID‐19 antivirals are needed urgently. Nirmatrelvir (PF‐07321332), the first orally bioavailable, severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) Mpro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. We report safety, tolerability, and pharmacokinetic data of nirmatrelvir with and without ritonavir as a pharmacokinetic enhancer, from an accelerated randomized, double‐blind, placebo‐controlled, phase I study. Two interleaving single‐ascending dose (SAD) cohorts were evaluated in a three‐period crossover. Multiple‐ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (b.i.d.) dosing was evaluated over 10 days in five parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase II/III clinical trials were supported by integrating modeling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). In SAD, MAD, and supratherapeutic exposure cohorts, nirmatrelvir/ritonavir was safe and well‐tolerated. Nirmatrelvir exposure and half‐life were considerably increased by ritonavir, enabling selection of nirmatrelvir/ritonavir dose and regimen for phase II/III trials (300/100 mg b.i.d.), to achieve concentrations continuously above those required for 90% inhibition of viral replication in vitro. The QSP model suggested that a 5‐day regimen would significantly decrease viral load in SARS‐CoV‐2‐infected patients which may prevent development of severe disease, hospitalization, and death. In conclusion, an innovative and seamless trial design expedited establishment of phase I safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase II/III dose selection and accelerated pivotal trials’ initiation (NCT04756531).
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Bergwerk M;Gonen T;Lustig Y;Amit S;Lipsitch M;Cohen C;Mandelboim M;Levin EG;Rubin C;Indenbaum V;Tal I;Zavitan M;Zuckerman N;Bar-Chaim A;Kreiss Y;Regev-Yochay G
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影响因子：
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