Pertinez, Henry, Rajoli, Rajith KR 
ORCID: 0000-0002-6015-5712, Khoo, Saye H ORCID: 0000-0002-2769-0967 and Owen, Andrew ORCID: 0000-0002-9819-7651
(2021)
Pharmacokinetic modelling to estimate intracellular favipiravir ribofuranosyl-5 '-triphosphate exposure to support posology for SARS-CoV-2.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 76 (8).
pp. 2121-2128.
|
Text
Pertinez-2021-Pharmacokinetic modelling to est.pdf - Published version Download (609kB) | Preview |
Abstract
<h4>Objectives</h4>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)].<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Animals, Dogs, Humans, Polyphosphates, Amides, Pyrazines, Antiviral Agents, COVID-19, SARS-CoV-2 |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology Faculty of Science and Engineering > School of Physical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 01 Nov 2021 08:43 |
| Last Modified: | 18 Jan 2023 21:25 |
| DOI: | 10.1093/jac/dkab135 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3142152 |
Dimensions
Dimensions
