Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2
Shadisadat Esmaeili, … , Stephen J. Polyak, Joshua T. Schiffer
Shadisadat Esmaeili, … , Stephen J. Polyak, Joshua T. Schiffer
Published September 11, 2025
Citation Information: J Clin Invest. 2025;135(21):e192052. https://doi.org/10.1172/JCI192052.
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Research Article Immunology Infectious disease Virology

Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2

Abstract

Molnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication. Molnupiravir reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral RNA levels in three separate trials. We used mathematical models to simulate these trials and closely recapitulated their virologic outcomes. Model simulations suggested lower antiviral potency against pre-Omicron SARS-CoV-2 variants than against Omicron. We estimated that in vitro assays underestimated in vivo potency by 6- to 7-fold against Omicron variants. Our model suggested that because polymerase chain reaction detects molnupiravir mutated variants, the true reduction in non-mutated viral RNA was underestimated by approximately 0.4 log10 in the two trials conducted while Omicron variants dominated. Viral area under the curve estimates differed significantly between non-mutated and mutated viral RNA. Our results reinforce past work suggesting that in vitro assays are unreliable for estimating in vivo antiviral drug potency and suggest that virologic endpoints for respiratory virus clinical trials should be catered to the drug mechanism of action.

Authors

Shadisadat Esmaeili, Katherine Owens, Ugo Avila-Ponce de Leon, Joseph F. Standing, David M. Lowe, Shengyuan Zhang, James A. Watson, William H.K. Schilling, Jessica Wagoner, Stephen J. Polyak, Joshua T. Schiffer

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Figure 1

Schematic of the viral dynamic model and molnupiravir PKPD model.

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Schematic of the viral dynamic model and molnupiravir PKPD model. (A) In...
(A) In the viral dynamic model, S represents the susceptible cells, IE is the eclipse infected cells, Ip is the productively infected cells, V is the non-mutated viruses, and Vm is the viruses mutated by treatment. The productively infected cells are cleared by early and late T cell–mediated immune response at rates δ and m(t). β is the infectivity rate, Φ is the rate of conversion of susceptible cells to refractory cells, and ρ is the rate of reversion of the refractory cells to susceptible cells. Productively infected cells produce viruses at the rate π, and free viruses are cleared at the rate γ. (B) Two-compartmental PK model with oral administration of the drug which models the amounts of the drug in gut tissue (AGI), plasma (AP), and the respiratory tract (AL). κa is the rate of absorption of the drug from gut to plasma, κPL and κLP are the rates of transfer of the drug from plasma to the respiratory tract and back, κCL and is the rate at which the drug clears from the body. Vol is the estimated plasma volume and Cp is the concentration of the drug in plasma. ε(Cp) is the efficacy of the drug in converting produced viruses into mutated, non-infectious viruses. Created in BioRender. https://BioRender.com/zm3u454.