Optimizing Hydroxychloroquine Dosing for Patients With COVID‐19: An Integrative Modeling Approach for Effective Drug Repurposing

Garcia‐Cremades, Maria; Solans, Belen P.; Hughes, Emma; Ernest, Jacqueline P.; Wallender, Erika; Aweeka, Francesca; Luetkemeyer, Anne F.; Savic, Radojka M.

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 (i) longitudinal clinical, pharmacokinetic (PK), and virologic data from patients with severe acute respiratory syndrome‐2 (SARS‐CoV‐2) infection who received HCQ with or without azithromycin (n = 116), (ii) in vitro viral replication data and SARS‐CoV‐2 viral load inhibition by HCQ, (iii) a population PK model of HCQ, and (iv) a model relating chloroquine PKs to corrected QT (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 PKs (P < 0.001). The extrapolated patient half‐maximal effective concentration (EC(50)) was 4.7 µM, comparable to the reported in vitro EC(50s). HCQ doses > 400 mg b.i.d. 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 with lower dose (≤ 400 mg daily) regimens. However, HCQ doses > 600 mg b.i.d. 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.