Pharmacokinetic modelling to estimate intracellular favipiravir ribofuranosyl-5′-triphosphate exposure to support posology for SARS-CoV-2
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
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.
Article activity feed
-
-
SciScore for 10.1101/2021.01.03.21249159: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources For catabolism/elimination experiments MDCK cells were incubated with favipiravir containing media at the specified concentrations for 24h to allow production and accumulation of FAVI-RTP, before the media was removed and replaced with favipiravir-free media. MDCKsuggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:The current approach has several …
SciScore for 10.1101/2021.01.03.21249159: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Experimental Models: Cell Lines Sentences Resources For catabolism/elimination experiments MDCK cells were incubated with favipiravir containing media at the specified concentrations for 24h to allow production and accumulation of FAVI-RTP, before the media was removed and replaced with favipiravir-free media. MDCKsuggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:The current approach has several important limitations that should be recognised. Favipiravir pharmacokinetic exposures have been demonstrated to be lower in American and African patients than in Chinese patients [28], and so the simulations may not be widely applicable across different ethnicities. The modelling applied a direct in vitro to in vivo extrapolation of kin and this should be considered as a major assumption as it directly presumes the in vitro Favimedia concentration is representative of free plasma concentration as derived from the PK model and that the umbrella kin parameter, which consolidates various underlying uptake and conversion processes, is directly translatable. Importantly, the presented intracellular predictions are specific to data generated on intracellular kinetics in MDCK cells. Therefore, accuracy of the intracellular FAVI-RTP concentrations will be dependent upon the similarity of relevant human in vivo cells in terms of the in vitro uptake/elimination as well as the rate and extent of metabolic activation of favipiravir to its triphosphorylated active form. Furthermore, there are no data with which to model the inter-patient variability in the intracellular uptake or conversion to FAVI-RTP and so intracellular concentration variability shown in Figure 3 is only derived from intracellular variability in plasma exposure. Finally, the intracellular prediction is driven by the estimated free plasma concentration, whereas in vivo it is possible lo...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
-
