tetano
Editor, Senior Moderator
Clin Pharmacol Ther. 2020 Apr 14. doi: 10.1002/cpt.1856. [Epub ahead of print]
Optimizing hydroxychloroquine dosing for patients with COVID-19: An integrative modeling approach for effective drug repurposing.
Garcia-Cremades M[SUP]1[/SUP], Solans BP[SUP]1[/SUP], Hughes E[SUP]1[/SUP], Ernest JP[SUP]1[/SUP], Wallender E[SUP]2[/SUP], Aweeka F[SUP]2[/SUP], Luetkemeyer A[SUP]3[/SUP], Savic RM[SUP]1[/SUP].
Author information
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 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 EC[SUB]50[/SUB] was 4.7 ?M, comparable to the reported in vitro EC[SUB]50[/SUB] '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.
This article is protected by copyright. All rights reserved.
KEYWORDS:
Infectious Disease; Pharmacokinetics-pharmacodynamics; Pharmacometrics; Translational pharmacokinetics-pharmacodynamics; Viral dynamics
PMID:32285930DOI:10.1002/cpt.1856
Optimizing hydroxychloroquine dosing for patients with COVID-19: An integrative modeling approach for effective drug repurposing.
Garcia-Cremades M[SUP]1[/SUP], Solans BP[SUP]1[/SUP], Hughes E[SUP]1[/SUP], Ernest JP[SUP]1[/SUP], Wallender E[SUP]2[/SUP], Aweeka F[SUP]2[/SUP], Luetkemeyer A[SUP]3[/SUP], Savic RM[SUP]1[/SUP].
Author information
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 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 EC[SUB]50[/SUB] was 4.7 ?M, comparable to the reported in vitro EC[SUB]50[/SUB] '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.
This article is protected by copyright. All rights reserved.
KEYWORDS:
Infectious Disease; Pharmacokinetics-pharmacodynamics; Pharmacometrics; Translational pharmacokinetics-pharmacodynamics; Viral dynamics
PMID:32285930DOI:10.1002/cpt.1856