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MICA: Pharmacokinetic/Pharmacodynamic (PKPD) Model Development to Inform SARS-CoV-2 Antiviral Development

MICA：药代动力学/药效 (PKPD) 模型开发为 SARS-CoV-2 抗病毒药物开发提供信息

基本信息

批准号：
MR/W015560/1
负责人：
Joseph Frank Standing
金额：
$ 30.09万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FW015560%2F1
关键词：
MICA Pharmacokinetic Pharmacodynamic PKPD Model

项目摘要

The COVID-19 pandemic has exposed two major weaknesses in our preparedness for respiratory viral threats. Firstly, there is a critical lack of available antiviral drugs which can be deployed at the first signs of symptoms or as post-exposure prophylaxis (given as a short course to people who have been in contact with an infected individual). Secondly, a basic principle of treating viral infections is that a combination of drugs with different modes of action is usually required, and for respiratory viruses, antiviral combinations are only effective if started in the first day or two following symptom onset. As with other respiratory viruses such as influenza, SARS-CoV-1 and MERS-CoV, SARS-CoV-2 viral replication rapidly slows following symptom onset with the later severe stage of disease mediated more by the body's response to the infection rather than active viral replication. Most clinical trials to-date have used single antiviral agents rather than combinations, and have studied hospitalised patients (i.e. late stage of the disease) when antivirals are unlikely to work. Most prioritised studies have been Phase III ttrials of agents that have not first been proven to reduce viral load in Phase II. Unsurprisingly, none of the repurposed monotherapies studied in this way have yet shown any benefit, and in the case of (hydroxy)chloroquine, have been proven to cause harm.There is an urgent need to rationally develop combination antivirals which reduce viral load, disease severity and risk of onward transmission. For vaccines, rational development meant small Phase II studies to assess antibody response, with successful vaccines taken forward to Phase III. The analogy for antivirals is small Phase II studies to find antiviral combinations that reduce viral load before progressing successful ones to Phase III. Repurposing trials such as RECOVERY and PRINCIPLE which took antiviral monotherapies with limited in vitro activity straight to Phase III have now comprehensively proven to be an inefficient way to find effective antiviral combinations. A more rational approach based on sound principles of antiviral drug development is now required.This work will focus on mathematical modelling of SARS-CoV-2 viral dynamics in order to optimally design and analyse the results for Phase II antiviral trials. Looking at the difference in viral load in patients receiving antivirals compared to placebo is complicated by the fact that in the normal course of the disease, viral load changes by the hour: after initial infection viral load in the nose and throat rises to a peak around the time of symptom onset, and then falls away again such that by Day 7 up to a third of people no longer have detectable virus. Viral load trajectories also differ in patients of different age, disease severity, and potentially when infected with different variants of the virus. Therefore a mathematical model of the expected time course is needed to tease out drug effects from these other variables. Using data we have collected during a recent individual patient-level meta analysis, we will firstly compare the performance of various recently published viral dynamic models on how they predict viral load with time. Using data from two ongoing Phase II trials, FLARE and FANTAZE, the models will be refined to account for new variants (both are double blind randomised trials with daily viral loads and whole genome viral sequencing) and to develop models of the repurposed drug combinations being tested (favipiravir, lopinavir/ritonavir and nitazoxanide). We will also work with Pfizer to apply these models to novel agents in their antiviral pipeline, and apply the models to real world data from three London hospitals to assess whether certain patient groups with prolonged viral shedding may benefit from antiviral treatment.The final output will be a modelling framework for the design and analysis of combination antiviral Phase II trials.

COVID-19疫情暴露了我们在应对呼吸道病毒威胁方面的两个主要弱点。首先，严重缺乏可在出现症状的最初迹象时使用或作为接触后预防（向与受感染者接触过的人提供短期治疗）的抗病毒药物。其次，治疗病毒感染的一个基本原则是，通常需要不同作用模式的药物组合，对于呼吸道病毒，只有在症状出现后的第一天或两天开始使用抗病毒组合才有效。与其他呼吸道病毒如流感、SARS-CoV-1和MERS-CoV一样，SARS-CoV-2病毒复制在症状发作后迅速减慢，疾病的后期严重阶段更多地由身体对感染的反应介导，而不是主动病毒复制。迄今为止，大多数临床试验使用单一抗病毒药物而不是组合药物，并研究了抗病毒药物不太可能起作用的住院患者（即疾病晚期）。最优先的研究是III期试验，这些试验的药物在II期试验中没有首先被证明可以降低病毒载量。不出所料，以这种方式研究的再利用的单一疗法中没有一种显示出任何益处，并且在（羟基）氯喹的情况下，已被证明会造成伤害。迫切需要合理开发联合抗病毒药物，以降低病毒载量，疾病严重程度和进一步传播的风险。对于疫苗，合理的开发意味着进行小型的II期研究以评估抗体反应，成功的疫苗将进入III期。对抗病毒药物的类比是小型II期研究，以找到在成功进入III期之前降低病毒载量的抗病毒组合。诸如RECOVERY和PRINCIPLE等将体外活性有限的抗病毒单一疗法直接用于III期的重新定位试验现已全面证明是寻找有效抗病毒组合的低效方法。现在需要一种基于抗病毒药物开发的合理原则的更合理的方法，这项工作将侧重于SARS-CoV-2病毒动力学的数学建模，以便最佳地设计和分析II期抗病毒试验的结果。观察接受抗病毒药物治疗的患者与安慰剂相比的病毒载量差异是复杂的，因为在疾病的正常过程中，病毒载量按小时变化：在初始感染后，鼻和喉中的病毒载量在症状发作时上升到峰值，然后福尔斯再次下降，到第7天，多达三分之一的人不再有可检测到的病毒。病毒载量轨迹在不同年龄、疾病严重程度的患者中也不同，并且可能在感染不同病毒变体时也不同。因此，需要一个预期时间过程的数学模型来从这些其他变量中梳理出药物效应。使用我们在最近的个体患者水平Meta分析中收集的数据，我们将首先比较各种最近发表的病毒动态模型如何预测病毒载量随时间的变化。使用来自两项正在进行的II期试验FLARE和FANTAZE的数据，将对模型进行改进，以解释新的变异（均为每日病毒载量和全基因组病毒测序的双盲随机试验），并开发正在测试的重新用途的药物组合（法匹拉韦，洛匹那韦/利托那韦和硝唑尼特）的模型。我们还将与辉瑞公司合作，将这些模型应用于其抗病毒产品线中的新型药物，并将这些模型应用于来自三家伦敦医院的真实的世界数据，以评估某些长期病毒脱落的患者群体是否可以从抗病毒治疗中获益。最终结果将是一个用于设计和分析联合抗病毒II期试验的建模框架。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Favipiravir, lopinavir-ritonavir, or combination therapy (FLARE): A randomised, double-blind, 2 × 2 factorial placebo-controlled trial of early antiviral therapy in COVID-19.

DOI：
10.1371/journal.pmed.1004120
发表时间：
2022-10
期刊：
PLOS MEDICINE
影响因子：
15.8
作者：
Lowe, David M.;Brown, Li-An K.;Chowdhury, Kashfia;Davey, Stephanie;Yee, Philip;Ikeji, Felicia;Ndoutoumou, Amalia;Shah, Divya;Lennon, Alexander;Rai, Abhulya;Agyeman, Akosua A.;Checkley, Anna;Longley, Nicola;Dehbi, Hakim-Moulay;Freemantle, Nick;Breuer, Judith;Standing, Joseph F.
通讯作者：
Standing, Joseph F.

Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial.