Chrome Extension
WeChat Mini Program
Use on ChatGLM
VIPCreated with Sketch.

    • Innovative Randomized Phase 1 Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir

    Ravi Shankar P. Singh,Sima S. Toussi,Frances Hackman, Phylinda L. Chan,Rohit Rao,Richard Allen,Lien Van Eyck,Sylvester Pawlak,Eugene P. Kadar, Frances Clark,Haihong Shi,Annaliesa S. Anderson,Michael Binks, Sandeep Menon,Gianluca Nucci,Arthur Bergman

    openalex（2022）

    Pfizer Worldwide Research | Pfizer Global Product Development | Pfizer Clinical Research Unit

    Cited 1|Views2
    Abstract
    ABSTRACT Background COVID-19 is a continued leading cause of hospitalization and death. Safe and efficacious COVID-19 antivirals are needed urgently. Nirmatrelvir (PF-07321332), the first orally bioavailable, SARS-CoV-2 M pro inhibitor against the coronaviridae family, has demonstrated potent preclinical antiviral activity and benign safety profile. Methods 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 1 study. Two interleaving single-ascending dose (SAD) cohorts were evaluated in a 3-period crossover. Multiple-ascending dose (MAD) with nirmatrelvir/ritonavir twice daily (BID) dosing was evaluated over 10 days in 5 parallel cohorts. Safety was assessed, including in a supratherapeutic exposure cohort. Dose and dosing regimen for clinical efficacy evaluation in phase 2/3 clinical trials were supported by integrating modelling and simulations of SAD/MAD data with nonclinical data and a quantitative systems pharmacology model (QSP). Results 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 2/3 trials (300/100 mg BID), 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 and prevent development of severe disease, hospitalization, and death. Conclusions An innovative and seamless trial design expedited establishment of phase 1 safety and pharmacokinetics of nirmatrelvir/ritonavir, enabling high confidence in phase 2/3 dose selection and accelerated pivotal trials’ initiation. NCT04756531
    More
    Translated text
    Key words
    Corona Virus
    PDF
    View via Publisher
    Bibtex
    AI Read Science
    AI Summary
    AI Summary is the key point extracted automatically understanding the full text of the paper, including the background, methods, results, conclusions, icons and other key content, so that you can get the outline of the paper at a glance.
    Example
    Background
    Key content
    Introduction
    Methods
    Results
    Related work
    Fund
    Key content
    • Pretraining has recently greatly promoted the development of natural language processing (NLP)
    • We show that M6 outperforms the baselines in multimodal downstream tasks, and the large M6 with 10 parameters can reach a better performance
    • We propose a method called M6 that is able to process information of multiple modalities and perform both single-modal and cross-modal understanding and generation
    • The model is scaled to large model with 10 billion parameters with sophisticated deployment, and the 10 -parameter M6-large is the largest pretrained model in Chinese
    • Experimental results show that our proposed M6 outperforms the baseline in a number of downstream tasks concerning both single modality and multiple modalities We will continue the pretraining of extremely large models by increasing data to explore the limit of its performance
    Try using models to generate summary,it takes about 60s
    Must-Reading Tree
    Example
    Generate MRT to find the research sequence of this paper
    Data Disclaimer
    The page data are from open Internet sources, cooperative publishers and automatic analysis results through AI technology. We do not make any commitments and guarantees for the validity, accuracy, correctness, reliability, completeness and timeliness of the page data. If you have any questions, please contact us by email: report@aminer.cn
    Chat Paper
    【要点】：本文报道了一项加速的随机、双盲、安慰剂对照的1期临床试验，研究了Nirmatrelvir与或不与ritonavir作为药代动力学增强剂的安全性和药代动力学数据，为后续2/3期临床试验的剂量选择提供了依据。
    

    【方法】：研究采用交叉设计，评估了两个单次递增剂量（SAD）队列和五个平行队列的多次递增剂量（MAD），并利用模型和模拟将SAD/MAD数据与非临床数据和定量系统药理学模型（QSP）相结合，以支持2/3期临床试验的剂量和方案选择。
    

    【实验】：在单次递增剂量、多次递增剂量和超治疗剂量暴露队列中，Nirmatrelvir/ritonavir均表现出安全性和良好的耐受性。Ritonavir显著增加了Nirmatrelvir的暴露和半衰期，从而为2/3期临床试验选定了300/100 mg BID的剂量和方案。QSP模型表明，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，防止严重疾病的发展、住院和死亡。所使用的数据集未在文中明确提及。临床试验注册号为NCT04756531。
    去 AI 文献库 对话