RESUMO
A key element for the prevention and management of COVID-19 is the development of effective therapeutics. Drug combination strategies of repurposed drugs offer several advantages over monotherapies, including the potential to achieve greater efficacy, the potential to increase the therapeutic index of drugs and the potential to reduce the emergence of drug resistance. Here, we report on the in vitro synergistic interaction between two FDA approved drugs, remdesivir and ivermectin resulting in enhanced antiviral activity against SARS-CoV-2. These findings warrant further investigations into the clinical potential of this combination, together with studies to define the underlying mechanism.
RESUMO
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.
