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Calibration and Validation of a Mechanistic COVID‐19 Model for Translational Quantitative Systems Pharmacology – A Proof‐of‐Concept Model Development for Remdesivir
Author(s) -
Samieegohar Mohammadreza,
Weaver James L.,
Howard Kristina E.,
Chaturbedi Anik,
Mann John,
Han Xiaomei,
Zirkle Joel,
Arabidarrehdor Ghazal,
Rouse Rodney,
Florian Jeffry,
Strauss David G.,
Li Zhihua
Publication year - 2022
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.2686
Subject(s) - clinical trial , drug development , medicine , disease , pharmacodynamics , antiviral drug , mechanism (biology) , covid-19 , drug , pharmacology , clinical pharmacology , clinical endpoint , intensive care medicine , computational biology , pharmacokinetics , infectious disease (medical specialty) , biology , philosophy , epistemology
With the ongoing global pandemic of coronavirus disease 2019 (COVID‐19), there is an urgent need to accelerate the traditional drug development process. Many studies identified potential COVID‐19 therapies based on promising nonclinical data. However, the poor translatability from nonclinical to clinical settings has led to failures of many of these drug candidates in the clinical phase. In this study, we propose a mechanism‐based, quantitative framework to translate nonclinical findings to clinical outcome. Adopting a modularized approach, this framework includes an in silico disease model for COVID‐19 (virus infection and human immune responses) and a pharmacological component for COVID‐19 therapies. The disease model was able to reproduce important longitudinal clinical data for patients with mild and severe COVID‐19, including viral titer, key immunological cytokines, antibody responses, and time courses of lymphopenia. Using remdesivir as a proof‐of‐concept example of model development for the pharmacological component, we developed a pharmacological model that describes the conversion of intravenously administered remdesivir as a prodrug to its active metabolite nucleoside triphosphate through intracellular metabolism and connected it to the COVID‐19 disease model. After being calibrated with the placebo arm data, our model was independently and quantitatively able to predict the primary endpoint (time to recovery) of the remdesivir clinical study, Adaptive Covid‐19 Clinical Trial (ACTT). Our work demonstrates the possibility of quantitatively predicting clinical outcome based on nonclinical data and mechanistic understanding of the disease and provides a modularized framework to aid in candidate drug selection and clinical trial design for COVID‐19 therapeutics.