16.04.2020
Optimizing hydroxychloroquine dosing for patients with COVID-19: An integrative modeling approach for effective drug repurposing
Therapeutic Transversal
Garcia-Cremades M et al
Clin Pharmacol Ther
Main result
The median effective concentration (EC50) extrapolated in vivo was 4.7 µM, comparable to those reported in vivo. Doses of more than 400 mg twice daily for at least 5 days would be expected to rapidly reduce viral loads, reduce the proportion of patients with detectable CoV-2 SARS infection, and shorten the duration of treatment compared to lower dose treatments (≤ 400 mg).
However, doses of HCQ > 600 mg twice daily would also be expected to prolong the QTc interval.
However, doses of HCQ > 600 mg twice daily would also be expected to prolong the QTc interval.
Takeaways
Low doses of hydroxychloroquine (400 mg once daily) may not be sufficient.
Doses higher than 400 mg twice a day would seem to be of value in reducing viral load.
Doses of HCQ > 600 mg twice daily could prolong the QTc interval.
Doses higher than 400 mg twice a day would seem to be of value in reducing viral load.
Doses of HCQ > 600 mg twice daily could prolong the QTc interval.
Strength of evidence Weak
1) Pre-proof
2) Models based on unreliable data (2 non-randomized studies with sometimes concomitant administration of azithromycin), assumption that lung concentration is equal to plasma concentration, assumption of a linear relationship between hydroxychloroquine dose and QTc prolongation, viral replication data based on SARS-CoV-1, ...
3) No exploration of digestive adverse effects, often reported as a reason for discontinuation of treatment".
Objectives
Integrate historical and emerging pharmacological and toxicity data to understand the safest and most effective dose of hydroxychloroquine for the management of COVID-19
Method
A pharmacokinetic ("PK") model: pharmacological / virological / QTc was developed and validated externally to predict the rate of SARS-CoV-2 viral decline and QTc prolongation.
Data included in the model :
1) Longitudinal clinical, pharmacokinetic and virological data from patients with SARS-CoV-2 who received HCQ with or without Azithromycin (n = 116)
2) in vitro viral replication data and inhibition of SARS-CoV-2 viral load by HCQ
3) a population pharmacokinetic model for Hydroxychloroquine
4) a model linking the pharmacokinetics of Chloroquine to QTc prolongation
Data included in the model :
1) Longitudinal clinical, pharmacokinetic and virological data from patients with SARS-CoV-2 who received HCQ with or without Azithromycin (n = 116)
2) in vitro viral replication data and inhibition of SARS-CoV-2 viral load by HCQ
3) a population pharmacokinetic model for Hydroxychloroquine
4) a model linking the pharmacokinetics of Chloroquine to QTc prolongation
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