Background: This goal of this analysis was to investigate the relationship of molnupiravir pharmacokinetics (PK) and clinical outcomes (primary endpoint of hospitalization or death) in patients with COVID-19 in the Phase 3 cohort of MOVe-OUT (clinicaltrials.gov NCT04577797).
Methods: Logistic regression models were constructed using a multi-step process with influential covariates identified first using placebo arm data only and subsequently assessment of drug effect as a function of exposures evaluated using placebo and MOV arm data. Individual estimates of exposure were derived from population PK modeling of sparse samples collected in all patients. All work was performed using R version 3.0 or later.
Results: A total of 1313 participants were included in the exposure-response (E-R) analysis, including subjects on MOV (N=630) and placebo (N=683). Participants with missing PK or baseline RNA were excluded (79 from MOV and 16 from placebo arms). The covariates shown to be significant determinants of response were baseline viral load, baseline disease severity, age, weight, viral clade, active cancer, and diabetic risk factors. An additive AUC-based Emax model with a fixed hill coefficient of 1 best represented exposure-dependency in drug effect. Estimated AUC50 was 19900 nM*hr with bootstrapped 95% confidence interval of (9270, 32700). Patients at 800 mg achieved near maximal response, which was larger than the response projected for 200 or 400 mg.
Conclusion: Overall, the E-R results support the MOV dose of 800 mg Q12H for treatment of COVID-19. Many patient characteristics, beyond drug exposures, impacted the risk of hospitalization or death.
Bernal, A.J. et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 386, 509-520 (2022).
