Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2
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
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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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 8

Relationship of drug pharmacokinetics and pharmacodynamics to in vivo potency and viral load reduction, comparing trial design.

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Relationship of drug pharmacokinetics and pharmacodynamics to in vivo po...
(A) Molnupiravir plasma concentration during 5 days of treatment with 800 mg molnupirvir given twice daily. The dashed lines mark the EC50 with different paf values that differ by trial. For paf = 0.13, drug levels are almost entirely above the EC50. (B) Dynamic shifts in molnupiravir efficacy for different paf values that differ by trial. Efficacy only drops minimally at trough levels when paf is low (i.e., 0.14 and 0.13 in PLATCOV and PANORAMIC) but drops significantly at trough levels in MOVe-OUT. (C) Drug potency of SARS-CoV-2 antivirals according to trial. The in vivo efficacy of molnupiravir in PLATCOV and PANORAMIC trials is close to the in vivo efficacy of nirmatrelvir/ritonavir in the PLATCOV trial and higher than EPIC-HR. MOVe-OUT potency is significantly lower due to a higher paf and higher in vivo EC50 value. (D) Simulated mean drops in total viral RNA from baseline relative to untreated arms on day 5 in the 3 molnupiravir trials and 2 nirmatrelvir/ritonavir trials. (E) Simulated mean drops in non-mutated viral RNA from baseline relative to counterfactual placebo on day 5 in the 3 molnupiravir trials and 2 nirmatrelvir/ritonavir trials. In the molnupiravir trials, total viral RNA drops less than non-mutated viral RNA due to PCR detection of drug-mutated viral RNA. Total possible reduction in non-mutated SARS-CoV-2 RNA is less for MOVe-OUT than PLATCOV and PANORAMIC due to higher initial viral loads and lower values of detection in the trials.