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Optimizing hydroxychloroquine dosing for patients with COVID-19: An integrative modeling approach for effective drug repurposing.
Hydroxychloroquine (HCQ) is a promising candidate for Coronavirus Disease of 2019 (COVID-19) treatment. The optimal dosing of HCQ is unknown. Our goal was to integrate historic and emerging pharmacological and toxicity data to understand safe and efficacious HCQ dosing strategies for COVID-19 treatment. The data sources included were 1) longitudinal clinical, pharmacokinetic, and virologic data from patients with severe acute respiratory syndrome-2 (SARS-CoV-2) infection who received HCQ with or without azithromycin (n=116), 2) in vitro viral replication data and SARS-CoV-2 viral load inhibition by HCQ, 3) a population pharmacokinetic model of HCQ and 4) a model relating chloroquine pharmacokinetics to QTc prolongation. A mechanistic PK/virologic/QTc model for HCQ was developed and externally validated to predict SARS-CoV-2 rate of viral decline and QTc prolongation. SARS-CoV-2 viral decline was associated with HCQ pharmacokinetics (p<0.001). The extrapolated patient EC50 was 4.7 µM, comparable to the reported in vitro EC50 's. HCQ doses > 400 mg BID for ≥5 days were predicted to rapidly decrease viral loads, reduce the proportion of patients with detectable SARS-CoV-2 infection, and shorten treatment courses, compared to lower dose (≤400 mg daily) regimens. However, HCQ doses >600 mg BID were also predicted to prolong QTc intervals. This prolongation may have clinical implications warranting further safety assessment. Due to COVID-19's variable natural history, lower dose HCQ regimens may be indistinguishable from controls. Evaluation of higher HCQ doses is needed to ensure adequate safety and efficacy.
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