A Pharmacokinetic Modeling Approach to Evaluate the Current Dosing Recommendations for Molnupiravir, a Novel Oral SARS-CoV-2 Antiviral, in the Egyptian Population

ABSTRACT

Introduction: Molnupiravir, a prodrug of the antiviral Nhydroxycytidine (NHC), is one of the limited treatment options that has recently gained emergency use authorization for treating mild-tomoderate SARS-CoV-2 cases. While NHC is shown to follow linear pharmacokinetics with similar exposures in healthy and SARS-CoV-2 subjects, its pharmacokinetics has not been characterized in the Egyptian population. Research Question or Hypothesis: We aimed to develop a population pharmacokinetic model for NHC and evaluate through simulations the current molnupiravir dosage of 800 mg twice daily for five days in the Egyptian population. Study Design: An open label, single arm pharmacokinetic study. Methods: Twelve healthy volunteers received 800 mg molnupiravir oral dose. Model development using non-linear mixed effect modeling and internal validation using bootstrapping and visual predictive check were conducted in MonolixSuite. Simulation-based maximum concentration (Cmax) 'the safety metric' and area under the curve (AUC0-12h) 'the efficacy metric' were computed for 1000 virtual subjects. Geometric mean ratios (GMR) and 90% confidence intervals (CI) compared to previously reported values were calculated. Results: A total of 132 NHC plasma concentrations were analyzed. Six transit compartments for absorption and one-compartment with weight on apparent clearance (CL/F) and volume of distribution (Vd/F) for disposition best described NHC's pharmacokinetics. The pharmackokinetic parameters were estimated with good precision and the population estimates for mean transit time, first-order absorption rate constant, CL/F and Vd/F were 0.49 hours, 2.32 hour-1, 75.12 L/hour.70 kg and 118 L/70 kg, respectively. Geometric means of simulation-based Cmax and AUC0-12 were 3827 ng/mL (GMR = 1.05;90% CI= 0.96-1.15) and 9320 ng.hr/mL (GMR = 1.04;90% CI= 0.97-1.11), respectively. Conclusion: Population pharmacokinetic model was developed for NHC. Simulations showed that current molnupiravir dosage can achieve the therapeutic targets and dose adjustment may not be required for the Egyptian population. The developed model could be used in the future to refine molnupiravir's dosage once further therapeutic targets are identified.