ABSTRACT
BackgroundThe role of favipiravir as a treatment for COVID-19 is unclear, with discrepant activity against SARS-CoV-2 in vitro, concerns about teratogenicity and pill burden, and an unknown optimal dose. In Vero-E6 cells, high concentrations are needed to inhibit SARS-CoV-2 replication. The purpose of this analysis was to use available data to simulate intracellular pharmacokinetics of favipiravir ribofuranosyl-5-triphosphate (FAVI-RTP) to better understand the putative applicability as a COVID-19 intervention. MethodsPreviously published in vitro data for the intracellular production and elimination of FAVI- RTP in MDCK cells incubated with parent favipiravir was fitted with a mathematical model to describe the time course of intracellular FAVI-RTP concentrations as a function of incubation concentration of parent favipiravir. Parameter estimates from this model fitting were then combined with a previously published population PK model for the plasma exposure of parent favipiravir in Chinese patients with severe influenza (the modelled free plasma concentration of favipiravir substituting for in vitro incubation concentration) to predict the human intracellular FAVI-RTP pharmacokinetics. ResultsIn vitro FAVI-RTP data was adequately described as a function of in vitro incubation media concentrations of parent favipiravir with an empirical model, noting that the model simplifies and consolidates various processes and is used under various assumptions and within certain limits. Parameter estimates from the fittings to in vitro data predict a flatter dynamic range of peak to trough for intracellular FAVI-RTP when driven by a predicted free plasma concentration profile. ConclusionThis modelling approach has several important limitations that are discussed in the main text of the manuscript. However, the simulations indicate that despite rapid clearance of the parent drug from plasma, sufficient intracellular FAVI-RTP may be maintained across the dosing interval because of its long intracellular half-life. Population average intracellular FAVI-RTP concentrations are estimated to maintain the Km for the SARS-CoV-2 polymerase for 3 days following 800 mg BID dosing and 9 days following 1200 mg BID dosing after a 1600 mg BID loading dose on day 1. Further evaluation of favipiravir as part of antiviral combinations for SARS-CoV-2 is warranted.
ABSTRACT
Chloroquine has attracted intense attention as a potential clinical candidate for prevention and treatment of COVID-19 based on reports of in-vitro efficacy against SARS-CoV-2. While the pharmacokinetic-pharmacodynamic (PK-PD) relationship of chloroquine is well established for malaria, there is sparse information regarding its dose-effect relationship in the context of COVID-19. Here, we explore the PK-PD relationship of chloroquine for COVID-19 by modelling both achievable systemic and pulmonary drug concentrations. Our data indicate that the standard anti-malarial treatment dose of 25mg/kg over three days does not deliver sufficient systemic drug exposures for the inhibition of viral replication. In contrast, PK predictions of chloroquine in the lungs using in-vivo data or human physiologically-based PK models, suggest that doses as low as 3mg/kg/day for 3 days could deliver exposures that are significantly higher than reported antiviral-EC90s for up to a week. Moreover, if pulmonary exposure is a driver for prevention, simulations show that chronic daily dosing of chloroquine may be unnecessary for prophylaxis purposes. Instead, once weekly doses of 5mg/kg would be sufficient to achieve a continuous cover of therapeutically active pulmonary exposures. These findings reveal a highly compartmentalised distribution of chloroquine in man that may significantly affect its therapeutic potential against COVID-19. The systemic circulation is shown as one site where chloroquine exposure is insufficient to inhibit SARS-CoV-2 replication. However, if therapeutic activity is driven by pulmonary exposure, it should be possible to reduce the chloroquine dose to safe levels. Carefully designed randomized controlled trials are urgently required to address these outstanding issues.