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Model-Informed Drug Repurposing: Viral Kinetic Modeling to Prioritize Rational Drug Combinations for COVID-19
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  • Michael Dodds,
  • Rajesh Krishna,
  • Antonio Gonclaves,
  • Craig Rayner
Michael Dodds
Certara LP
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Rajesh Krishna
Certara LP
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Antonio Gonclaves
INSERM
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Craig Rayner
Certara LP
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Abstract

Aim: We hypothesize that the efficacy of COVID-19 therapeutic candidates will be better predicted by understanding their effects at various points on a viral cell cycle, in particular, the specific rate constants, and that drugs acting independently of these specific discrete sites may not yield expected efficacy. We hypothesize that drugs, or combinations of drugs that act at specific multiple sites on the viral life cycle have the highest probability of success in the treatment of early infection phase in COVID-19 patients. Methods: Using a target cell limited model structure that had been used to characterize viral load dynamics from COVID-19 patients, we performed simulations to show that combinations of therapeutics targeting specific rate constants have greater probability of efficacy and supportive rationale for clinical trial evaluation. Results: Based on the known kinetics of the SARS-CoV-2 life cycle, we rank ordered potential targeted approaches involving repurposed, low-potency agents. We suggest that targeting multiple points central to viral replication within infected host cells or release from those cells is a viable strategy for reducing both viral load and host cell infection. In addition, we observed that the time-window opportunity for a therapeutic intervention to effect duration of viral shedding exceeds the effect on sparing epithelial cells from infection or impact on viral load AUC. Furthermore, the impact on reduction on duration of shedding may extend further in patients who exhibit a prolonged shedder phenotype. Conclusions: Our work highlights the use of model-informed tools to better rationalize effective treatments for COVID-19.

Peer review status:Published

11 Jun 2020Submitted to British Journal of Clinical Pharmacology
12 Jun 2020Submission Checks Completed
12 Jun 2020Assigned to Editor
12 Jun 2020Reviewer(s) Assigned
26 Jun 2020Review(s) Completed, Editorial Evaluation Pending
26 Jun 2020Editorial Decision: Revise Major
28 Jun 20201st Revision Received
29 Jun 2020Assigned to Editor
29 Jun 2020Submission Checks Completed
29 Jun 2020Review(s) Completed, Editorial Evaluation Pending
29 Jun 2020Reviewer(s) Assigned
30 Jun 2020Editorial Decision: Revise Major
30 Jun 20202nd Revision Received
30 Jun 2020Assigned to Editor
30 Jun 2020Submission Checks Completed
30 Jun 2020Review(s) Completed, Editorial Evaluation Pending
30 Jun 2020Editorial Decision: Accept
21 Jul 2020Published in British Journal of Clinical Pharmacology. 10.1111/bcp.14486