Population Pharmacokinetics of Hydroxychloroquine in COVID-19 Patients: Implications for Dose Optimization
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ORIGINAL RESEARCH ARTICLE
Population Pharmacokinetics of Hydroxychloroquine in COVID‑19 Patients: Implications for Dose Optimization Pauline Thémans1 · Leila Belkhir2 · Nicolas Dauby3,4 · Jean‑Cyr Yombi2 · Julien De Greef2 · Kevin‑Alexandre Delongie5 · Martin Vandeputte4 · Rakan Nasreddine3 · Xavier Wittebole2 · Francoise Wuillaume4 · Cécile Lescrainier6 · Veerle Verlinden6 · Sophie Kiridis6 · Jean‑Michel Dogné6,7 · Jamila Hamdani6 · Pierre Wallemacq5 · Flora T. Musuamba6,8
© Springer Nature Switzerland AG 2020
Abstract Background and Objective In the absence of characterization on pharmacokinetics and reference concentrations for hydroxychloroquine in COVID-19 patients, the dose and treatment duration for hydrochloroquine are currently empirical, mainly based on in vitro data, and may vary across national guidelines and clinical study protocols. The aim of this paper is to describe the pharmacokinetics of hydroxychloroquine in COVID-19 patients, considered to be a key step toward its dosing optimization. Methods We have developed a population pharmacokinetic model for hydroxychloroquine in COVID-19 patients using prospectively collected pharmacokinetic data from patients either enrolled in a clinical trial or treated with hydroxychloroquine as part of standard of care in two tertiary Belgian hospitals. Results The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination. The estimated parameter values were 9.3/h, 860.8 L, and 15.7 L/h for the absorption rate constant, the central compartment volume, and the clearance, respectively. The bioavailability factor was fixed to 0.74 based on previously published models. Model validations by bootstraps, prediction corrected visual predictive checks, and normalized prediction distribution errors gave satisfactory results. Simulations were performed to compare the exposure obtained with alternative dosing regimens. Conclusion The developed models provide useful insight for the dosing optimization of hydroxychloroquine in COVID-19 patients. The present results should be used in conjunction with exposure-efficacy and exposure-safety data to inform optimal dosing of hydroxychloroquine in COVID-19.
Pauline Thémans and Leila Belkhir have equally contributed to the manuscript. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13318-020-00648-y) contains supplementary material, which is available to authorized users. * Flora T. Musuamba Flora.MusuambaTshinanu@fagg‑afmps.be Extended author information available on the last page of the article Vol.:(0123456789)
P. Thémans et al.
Key Points Inconsistent doses of hydroxychloroquine are included in national guidelines and clinical study protocols for the management of COVID-19 disease Modeling and simulation approaches have recently been proposed for dose selection, but (external) clinical validation was either lacking or carrying important limitations and unverified assumptions We propose a population pharmacokinetic m
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