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

Clin Pharmacol Ther. 2020 Aug;108(2):253-263. doi: 10.1002/cpt.1856. Epub 2020 May 12.

Abstract

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 (EC50 ) was 4.7 µM, comparable to the reported in vitro EC50s . 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.

MeSH terms

  • Antiviral Agents / administration & dosage
  • Antiviral Agents / pharmacokinetics
  • Betacoronavirus / drug effects*
  • Betacoronavirus / physiology
  • COVID-19 / drug therapy
  • Coronavirus Infections / drug therapy
  • Coronavirus Infections / virology
  • Drug Repositioning
  • Humans
  • Hydroxychloroquine / administration & dosage*
  • Hydroxychloroquine / pharmacokinetics*
  • Models, Biological
  • Reproducibility of Results
  • SARS Virus / drug effects
  • SARS Virus / physiology
  • SARS-CoV-2
  • Translational Medical Research
  • Viral Load / drug effects
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Hydroxychloroquine

Supplementary concepts

  • COVID-19 drug treatment