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.
RESUMO
There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against SARS-CoV-2. However, this has not been accompanied by a comprehensive evaluation of the ability of these drugs to achieve target plasma and lung concentrations following approved dosing in humans. Moreover, most publications have focussed on 50% maximum effective concentrations (EC50), which may be an insufficiently robust indicator of antiviral activity because of marked differences in the slope of the concentration-response curve between drugs. Accordingly, in vitro anti-SARS-CoV-2 activity data was digitised from all available publications up to 13th April 2020 and used to recalculate an EC90 value for each drug. EC90 values were then expressed as a ratio to the achievable maximum plasma concentrations (Cmax) reported for each drug after administration of the approved dose to humans (Cmax/EC90 ratio). Only 14 of the 56 analysed drugs achieved a Cmax/EC90 ratio above 1 meaning that plasma Cmax concentrations exceeded those necessary to inhibit 90% of SARS-CoV-2 replication. A more in-depth assessment of the putative agents tested demonstrated that only nitazoxanide, nelfinavir, tipranavir (boosted with ritonavir) and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval at their approved human dose. For all drugs reported, the unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated and used along with reported Cmax and fraction unbound in plasma to derive a lung Cmax/EC50 as a better indicator of potential human efficacy (lung Cmax/EC90 ratio was also calculable for a limited number of drugs). Using this parameter hydroxychloroquine, chloroquine, mefloquine, atazanavir (boosted with ritonavir), tipranavir (boosted with ritonavir), ivermectin, azithromycin and lopinavir (boosted with ritonavir) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50. This analysis was not possible for nelfinavir because insufficient data were available to calculate KpUlung but nitozoxanide and sulfadoxine were also predicted to exceed their reported EC50 by 3.1- and 1.5-fold in lung, respectively. The antiviral activity data reported to date have been acquired under different laboratory conditions across multiple groups, applying variable levels of stringency. However, this analysis may be used to select potential candidates for further clinical testing, while deprioritising compounds which are unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments such as the lung, in order to maximise the potential for success of proposed human clinical trials.