Model informed dosing of Hydroxycholoroquine in COVID-19 patients: Learnings from the recent experience, remaining uncertainties and Gaps

Thémans, Pauline; Dauby, Nicolás; Schrooyen, Loïc; Lebout, Faustine; Delforge, Marc; Nasreddine, Rakan; Libois, Agnès; Payen, Marie-Christine; Konopnicki, Déborah; Wuillaume, F; Lescrainier, Cécile; Verlinden, Veerle; Dogné, Jean‐Michel; Hamdani, Jamila; Musuamba, Flora T.

doi:10.22541/au.158801918.87109358

Cited by 3 publications

(8 citation statements)

References 16 publications

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“…Body weight was found to exert a significant influence on drug clearance. This is in accordance with the findings reported by Themans et al, 22 and by Morita et al 13 Thus, weight-based dosage regimens would help maintain blood concentrations within the desired range. In the published simulation-based studies, 29,30 the proposed dosing regimen for the prevention and treatment of COVID-19 was based on a previously developed model for HCQ in patients with malaria.…”

Section: Discussionsupporting

confidence: 92%

“…Body weight was found to exert a significant influence on drug clearance. This is in accordance with the findings reported by Themans et al, 22 and by Morita et al 13 . Thus, weight‐based dosage regimens would help maintain blood concentrations within the desired range.…”

Section: Discussionsupporting

confidence: 92%

“…Several popPK models have been published for HCQ and the recent work reported by Themans et al focused on dose optimization of HCQ in COVID-19 patients. 22 Among the identified literature, models were developed using whole-blood concentrations, plasma concentrations, and both plasma and whole blood obtained from patients being treated for various conditions. Plasma concentrations of HCQ are more variable and it has been recommended that HCQ whole-blood concentrations should be preferred over plasma.…”

Section: Discussionmentioning

confidence: 99%

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Population Pharmacokinetics of Hydroxychloroquine Sulfate in Healthcare Workers, Given for Prophylaxis Against Coronavirus Disease 2019 (COVID‐19) in India

Raj

Gogtay

Pandey

et al. 2022

The Journal of Clinical Pharma

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Healthcare workers (HCWs) and frontline workers were recommended hydroxychloroquine (HCQ) 400 mg twice a day on day 1, followed by 400 mg once weekly for the next 7 weeks, as prophylaxis against COVID‐19. There was limited information on the population pharmacokinetics (popPK) of HCQ in an Indian setting when administered for prophylaxis against COVID‐19, and hence this study was proposed. It was a multicentric prospective study conducted at 3 sites in India wherein HCWs who were already on HCQ prophylaxis, who were about to start prophylaxis or who had stopped the prophylaxis for any reason were enrolled. Each participant gave 2 to 6 blood samples at different time points and whole‐blood HCQ concentrations were assayed using liquid chromatography with tandem mass spectrometry (LC MS/MS). popPK analysis was performed using PUMAS 1.1.0. A total of N = 338 blood samples from N = 121 participants were included in the popPK analysis. A 2‐compartment structural model with linear elimination was able to explain the observed data. Body weight was found to be a significant covariate influencing drug clearance. The final model was assessed using goodness‐of‐fit plots, a visual predictive check and a bootstrap, all of which confirmed that the model was appropriate. Simulations based on the current regimen showed that trough values were below the half‐maximal effective concentration (EC50) of 0.7 μmol against COVID‐19. A new weight‐based dosage regimen was proposed to maintain the trough concentration above the EC50 threshold.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Population Pharmacokinetics of Hydroxychloroquine Sulfate in Healthcare Workers, Given for Prophylaxis Against Coronavirus Disease 2019 (COVID‐19) in India

Raj

Gogtay

Pandey

et al. 2022

The Journal of Clinical Pharma

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“…Six POPPK models are available in the literature for HCQ. [ 1 – 3 , 20 , 21 ] Two of these were developed using whole-blood HCQ concentrations in patients with RA [ 2 ] and CLE [ 3 ]. The four additional models describe plasma concentrations, or merged blood and plasma concentrations, in different indications [ 1 , 3 , 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…There is an urgent need for HCQ pharmacokinetic characterization in COVID-19, as acknowledged in recent publications. [ 18 – 20 ].…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetics of Hydroxychloroquine in COVID-19 Patients: Implications for Dose Optimization

Thémans

Belkhir

Dauby

et al. 2020

Eur J Drug Metab Pharmacokinet

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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. Electronic supplementary material The online version of this article (10.1007/s13318-020-00648-y) contains supplementary material, which is available to authorized users.

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Systemic exposure to hydroxychloroquine and its relationship with outcome in severely ill COVID‐19 patients in New York City

Lyashchenko

McMahon

et al. 2022

Brit J Clinical Pharma

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Aim To investigate the relationship between systemic exposure to hydroxychloroquine (HCQ) and its metabolite desethylhydroxychloroquine (DHCQ) and clinical outcome in severely ill patients treated with a standard oral dose regimen of HCQ during the first wave of COVID‐19 in New York City. Methods We correlated retrospective clinical data with drug exposure prospectively assessed from convenience samples using population pharmacokinetics and Bayesian estimation. Systemic exposure was assessed in 215 patients admitted to ICU or COVID‐ward for whom an interleukin‐6 level was requested and who were still alive 24 hours after the last dose of HCQ. Patients received oral HCQ 600 mg twice daily on day 1 followed by 4 days of 400 mg daily. Results Fifty‐three precent of the patients were intubated at 5.4 ± 6.4 days after admission and 26.5% died at an average of 32.2 ± 19.1 days. QTc at admission was 448 ± 34 ms. Systemic exposure to HCQ and DHCQ demonstrated substantial variability. Cumulative area under the serum concentration–time curve up to infinity for HCQ was 71.4 ± 19.3 h mg/L and for DHCQ 56.5 ± 28.3 h mg/L. Variability in systemic exposure was not clearly explained by renal function, liver function or inflammatory state. In turn, systemic exposure did not correlate with intubation status, survival or QTc prolongation. Conclusion This study in severely ill patients was not able to find any relationship between systemic exposure to HCQ and DHCQ and clinical outcome at a routine dose regimen and adds to the growing body of evidence that oral HCQ does not alter the course of disease in COVID‐19 patients.

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Model informed dosing of Hydroxycholoroquine in COVID-19 patients: Learnings from the recent experience, remaining uncertainties and Gaps

Cited by 3 publications

References 16 publications

Population Pharmacokinetics of Hydroxychloroquine Sulfate in Healthcare Workers, Given for Prophylaxis Against Coronavirus Disease 2019 (COVID‐19) in India

Population Pharmacokinetics of Hydroxychloroquine Sulfate in Healthcare Workers, Given for Prophylaxis Against Coronavirus Disease 2019 (COVID‐19) in India

Population Pharmacokinetics of Hydroxychloroquine in COVID-19 Patients: Implications for Dose Optimization

Systemic exposure to hydroxychloroquine and its relationship with outcome in severely ill COVID‐19 patients in New York City

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