Factors Influencing COVID-19 Risk: Insights from Molnupiravir Exposure-Response Modeling of Clinical Outcomes.

Molnupiravir (MOV) is an oral antiviral for the treatment of COVID-19 in outpatient settings. This analysis investigated the relationship between β-D-N4-hydroxycytidine (NHC) pharmacokinetics (PK) and clinical outcomes in patients with mild to moderate COVID-19 in the Phase 3 part of the randomized, double-blind, placebo-controlled MOVe-OUT trial. Logistic regression models of the dependency of outcomes on exposures and covariates were constructed using a multi-step process. Influential covariates were identified first using placebo arm data, followed by assessment of exposure-dependency in drug effect using data from both the placebo and MOV arms. The exposure-response (E-R) analysis included 1,313 participants; 630 received MOV and 683 received placebo. Baseline viral load, baseline disease severity, age, weight, viral clade, active cancer, and diabetes were identified as significant determinants of response using placebo data. Absolute measures of viral load on days 5 and 10 were strong on-treatment predictors of hospitalization. An additive area under the curve (AUC)-based E max model with a fixed Hill coefficient of 1 best represented the exposure-dependency in drug effect and the AUC50 was estimated to be 19,900 nM*hr. Patients at 800 mg achieved near maximal response which was larger than for 200 or 400 mg. The final E-R model was externally validated and predicted that the relative reduction in hospitalization with MOV treatment would vary with patient characteristics and factors in the population. In conclusion, the E-R results support the MOV dose of 800 mg twice daily to treat COVID-19. Many patient characteristics and factors impacted outcomes beyond drug exposures.