A population pharmacokinetic modeling approach to evaluate the current dosing recommendations of favipiravir in egyptian subjects

Intro: Favipiravir is approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) for managing emerging influenza and is under investigation for treating SARS-CoV-2 cases. While favipiravir's pharmacokinetics is similar between healthy and infected subjects, a previous study reported potential racial differences in favipiravir's exposures which may affect reaching therapeutic concentrations. Herein, we developed a population pharmacokinetic model and assessed through simulations the PMDA-approved favipiravir's dosage in achieving therapeutic targets in Egyptian subjects. Methods: Twenty-five healthy subjects received a 200 mg favipiravir dose. Nonlinear mixed effect modeling was used for model development and validation. Post-hoc individual pharmacokinetic parameter estimates were used in simulations to evaluate the recommended dosage of 1600 mg twice daily on day one followed by 600 mg twice daily for four days. Therapeutic target was defined as trough concentrations > 20 mg/L at every time point following the second dose which was shown previously to improve clinical outcomes for influenza. Findings: A total of 550 favipiravir plasma concentrations were analyzed. A two- compartment disposition model with simultaneous zero and first-order absorption processes adequately described favipiravir's pharmacokinetics. The typical estimates for apparent clearance (CL/F) and total volume of distribution were 19.8 L/hour (95% confidence interval (CI) = 15.9-22.4) and 34.1 L (95% CI = 27.7-39.9), respectively. The Egyptian subjects had 2-fold (95% CI= 1.68-2.5) higher CL/F compared to the previously reported value in Japanese subjects. Therapeutic target was not achieved in any Egyptian subject. Discussion: Our findings match a previous study demonstrating that United States subjects had approximately 1.6-fold higher CL/F compared to Japanese subjects. The current study further supports the racial differences in favipiravir pharmacokinetics. Conclusion: Simulations showed that PMDA-approved favipiravir's dosage cannot achieve the therapeutic target and dose modification could be required for the Egyptian subjects. The developed model could be used to predict the effective favipiravir dose in future clinical trials.