Pharmacokinetic Modelling to Estimate Intracellular Favipiravir Ribofuranosyl-5'-triphosphate Exposure to Support Posology for SARS-CoV-2

Overview

Journal J Antimicrob Chemother

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2021 Jun 2

PMID 34075418

Citations 9

Authors

Henry Pertinez

Rajith K R Rajoli

Saye H Khoo

Andrew Owen

Affiliations

Soon will be listed here.

Abstract

Objectives: Favipiravir has discrepant activity against SARS-CoV-2 in vitro, concerns about teratogenicity and pill burden, and an unknown optimal dose. This analysis used available data to simulate the intracellular pharmacokinetics of the favipiravir active metabolite [favipiravir ribofuranosyl-5'-triphosphate (FAVI-RTP)].

Methods: Published in vitro data for intracellular production and elimination of FAVI-RTP in Madin-Darby canine kidney cells were fitted with a mathematical model describing the time course of intracellular FAVI-RTP as a function of favipiravir concentration. Parameter estimates were then combined with a published population pharmacokinetic model in Chinese patients to predict human intracellular FAVI-RTP. In vitro FAVI-RTP data were adequately described as a function of concentrations with an empirical model, noting simplification and consolidation of various processes and several assumptions.

Results: Parameter estimates from fittings to in vitro data predict a flatter dynamic range of peak to trough for intracellular FAVI-RTP (peak to trough ratio of ∼1 to 1) when driven by a predicted free plasma concentration profile, compared with the plasma profile of parent favipiravir (ratio of ∼2 to 1). This approach has important assumptions, but indicates that, despite rapid clearance of the parent from plasma, sufficient intracellular FAVI-RTP may be maintained across the dosing interval because of its long intracellular half-life.

Conclusions: Population mean intracellular FAVI-RTP concentrations are estimated to be maintained above the Km for the SARS-CoV-2 polymerase for 9 days with a 1200 mg twice-daily regimen (following a 1600 mg twice-daily loading dose on day 1). Further evaluation of favipiravir as part of antiviral combinations for SARS-CoV-2 is warranted.

Citing Articles

Favipiravir pharmacokinetics in Thai adults with mild COVID-19: A sub-study of interpatient variability and ethnic differences in exposure.

Prasanchaimontri I, Manosuthi W, Pertinez H, Owen A, Niyomnaitham S, Sirijatuphat R Pharmacol Res Perspect. 2024; 12(6):e1233.

PMID: 39509583 PMC: 11542727. DOI: 10.1002/prp2.1233.

Chemoprophylactic Assessment of Combined Intranasal SARS-CoV-2 Polymerase and Exonuclease Inhibition in Syrian Golden Hamsters.

Gallardo-Toledo E, Neary M, Sharp J, Herriott J, Kijak E, Bramwell C Viruses. 2023; 15(11).

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Favipiravir treatment in non-severe COVID-19: promising results from multicenter propensity score-matched study (FAVICOV).

Siripongboonsitti T, Muadchimkaew M, Tawinprai K, Issaranon O, Meepholkij W, Arttawejkul P Sci Rep. 2023; 13(1):14884.

PMID: 37689754 PMC: 10492810. DOI: 10.1038/s41598-023-42195-x.

The Real-World Clinical Outcomes of Favipiravir Treatment with Telemedicine Monitoring in Preventing Disease Progression in Mild to Moderate COVID-19 Patients; A Retrospective Cohort Study.

Siripongboonsitti T, Tawinprai K, Cheirsilpa K, Ungtrakul T, Krisorakun W, Chotipanich C Medicina (Kaunas). 2023; 59(6).

PMID: 37374302 PMC: 10303028. DOI: 10.3390/medicina59061098.

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Yadav P, Chowdhury P Heliyon. 2022; 8(12):e12327.

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