Need for a Standardized Translational Drug Development Platform: Lessons Learned from the Repurposing of Drugs for COVID-19.
Need for a Standardized Translational Drug Development Platform: Lessons Learned from the Repurposing of Drugs for COVID-19.
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DOI：
10.3390/microorganisms10081639
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发表时间：
2022-08-12
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
在缺乏治疗或预防COVID-19的药物的情况下，药物再利用可能是一种有价值的策略。尽管有大量的临床试验，药物再利用并没有兑现其承诺。虽然观察到一些改变用途的药物取得了成功（例如，Remdesivir、地塞米松、托珠单抗、baricitinib），其他药物未能显示临床疗效。一个原因是缺乏明确的翻译过程的基础上充分的临床前分析之前，临床评价。结合现有的体外和体内模型的局限性，在全球大流行的背景下，迫切需要一种系统的方法来开发抗病毒药物。我们实施了一种方法来测试再利用和实验药物，为进一步的临床开发提供强大的临床前证据。该转化药物开发平台包括SARS-CoV-2的体外、离体和体内模型，沿着药代动力学建模和模拟方法，以评估血浆和靶器官中的暴露水平。在此，我们提供了在我们的多学科合作中测试的已确定的重新利用的抗病毒药物的例子，以强调在COVID-19大流行期间紧急抗病毒药物开发中吸取的经验教训。我们的数据证实了在多种测定中评估体外和体内效力以提高临床前数据的可翻译性的重要性。药代动力学建模和模拟的化合物优先级的价值进行了讨论。我们主张需要针对轻度至中度COVID-19建立标准化转化药物开发平台，以生成支持临床试验的临床前证据。我们提出了明确的先决条件，用于临床试验的候选药物的进展。需要进一步的研究来更深入地了解所提出的转化药物开发平台的范围和局限性。
In the absence of drugs to treat or prevent COVID-19, drug repurposing can be a valuable strategy. Despite a substantial number of clinical trials, drug repurposing did not deliver on its promise. While success was observed with some repurposed drugs (e.g., remdesivir, dexamethasone, tocilizumab, baricitinib), others failed to show clinical efficacy. One reason is the lack of clear translational processes based on adequate preclinical profiling before clinical evaluation. Combined with limitations of existing in vitro and in vivo models, there is a need for a systematic approach to urgent antiviral drug development in the context of a global pandemic. We implemented a methodology to test repurposed and experimental drugs to generate robust preclinical evidence for further clinical development. This translational drug development platform comprises in vitro, ex vivo, and in vivo models of SARS-CoV-2, along with pharmacokinetic modeling and simulation approaches to evaluate exposure levels in plasma and target organs. Here, we provide examples of identified repurposed antiviral drugs tested within our multidisciplinary collaboration to highlight lessons learned in urgent antiviral drug development during the COVID-19 pandemic. Our data confirm the importance of assessing in vitro and in vivo potency in multiple assays to boost the translatability of pre-clinical data. The value of pharmacokinetic modeling and simulations for compound prioritization is also discussed. We advocate the need for a standardized translational drug development platform for mild-to-moderate COVID-19 to generate preclinical evidence in support of clinical trials. We propose clear prerequisites for progression of drug candidates for repurposing into clinical trials. Further research is needed to gain a deeper understanding of the scope and limitations of the presented translational drug development platform.
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影响因子：
5.9
作者：
Cochin M;Luciani L;Touret F;Driouich JS;Petit PR;Moureau G;Baronti C;Laprie C;Thirion L;Maes P;Boudewijns R;Neyts J;de Lamballerie X;Nougairède A
通讯作者：
Nougairède A
影响因子：
4
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Barnes, Geoffrey D.;Burnett, Allison;Allen, Arthur;Ansell, Jack;Blumenstein, Marilyn;Clark, Nathan P.;Crowther, Mark;Dager, William E.;Deitelzweig, Steven B.;Ellsworth, Stacy;Garcia, David;Kaatz, Scott;Raffini, Leslie;Rajasekhar, Anita;Van Beek, Andrea;Minichiello, Tracy
通讯作者：
Minichiello, Tracy
影响因子：
39
作者：
Clemency, Brian M.;Varughese, Renoj;Blaiss, Michael S.
通讯作者：
Blaiss, Michael S.
影响因子：
16.6
作者：
Abdelnabi R;Foo CS;Jochmans D;Vangeel L;De Jonghe S;Augustijns P;Mols R;Weynand B;Wattanakul T;Hoglund RM;Tarning J;Mowbray CE;Sjö P;Escudié F;Scandale I;Chatelain E;Neyts J
通讯作者：
Neyts J
影响因子：
2.8
作者：
Chavda VP;Kapadia C;Soni S;Prajapati R;Chauhan SC;Yallapu MM;Apostolopoulos V
通讯作者：
Apostolopoulos V