Towards Optimization of Hydroxychloroquine Dosing in Intensive Care Unit COVID-19 Patients

Périnel, Sophie; Launay, Manon; Botelho-Nevers, Élisabeth; Diconne, Éric; Louf-Durier, Aurore; Lachand, Raphael; Murgier, Martin; Page, Dominique; Vermesch, R.; Thierry, Guillaume; Delavenne, Xavier

doi:10.1093/cid/ciaa394

Cited by 87 publications

(106 citation statements)

References 9 publications

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“…Similar to what has been proposed for treatment by other groups, 4,5 our simulations suggest higher treatment and prophylactic doses for COVID‐19 may be needed than those recommended for malaria. This is consistent with the > 20‐fold lower in vitro EC 50 for malaria compared with SARS‐CoV‐2 13 .…”

Section: Discussionsupporting

confidence: 80%

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Finding the Dose for Hydroxychloroquine Prophylaxis for COVID‐19: The Desperate Search for Effectiveness

Al‐Kofahi

Jacobson

Boulware

et al. 2020

Clin Pharma and Therapeutics

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Hydroxychloroquine is an antimalarial drug being tested as a potential treatment for the novel coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2. Although the efficacy of hydroxychloroquine for COVID-19 remains uncertain, it may serve as a potential prophylactic agent especially in those at high risk, such as healthcare workers, household contacts of infected patients, and the immunocompromised. Our aim was to identify possible hydroxychloroquine dosing regimens through simulation in those at high risk of infections by optimizing exposures above the in vitro generated half maximal effective concentration (EC 50 ) and to help guide researchers in dose-selection for COVID-19 prophylactic studies. To maintain weekly troughs above EC 50 in > 50% of subjects at steady-state in a pre-exposure prophylaxis setting, an 800 mg loading dose followed by 400 mg twice or 3 times weekly is required. In an exposure driven, postexposure prophylaxis setting, 800 mg loading dose followed in 6 hours by 600 mg, then 600 mg daily for 4 more days achieved daily troughs above EC 50 in > 50% subjects. These doses are higher than recommended for malaria chemoprophylaxis, and clinical trials are needed to establish safety and efficacy.

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Section: Discussionsupporting

confidence: 80%

“…There are no scientifically established doses for SARS‐CoV‐2. Although pharmacometric modeling and simulation has been used by several groups to propose potential regimens, 3–5 these are targeted for hospitalized patients with advanced disease and no models have specifically evaluated regimens in the context of prophylaxis.…”

mentioning

confidence: 99%

Finding the Dose for Hydroxychloroquine Prophylaxis for COVID‐19: The Desperate Search for Effectiveness

Al‐Kofahi

Jacobson

Boulware

et al. 2020

Clin Pharma and Therapeutics

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“…The clinical pharmacology community is rapidly addressing these uncertainties using quantitative translational tools (e.g., physiologically-based pharmacokinetics, population pharmacokinetics, and mechanism-based viral dynamics), as exemplified in recent reports aimed at optimizing hydroxychloroquine dosage. 4,5,6 A recent report of population pharmacokinetics in the critical care setting indicated the variable pharmacokinetic performance of different investigational hydroxychloroquine dosing regimens. 5 Dose selection will also need to consider QT prolongation by this drug and associated proarrhythmic risk.…”

Section: Dosage Of Covid-19 Treatmentsmentioning

confidence: 99%

Challenges in Drug Development Posed by the COVID‐19 Pandemic: An Opportunity for Clinical Pharmacology

Venkatakrishnan

Yalkinoglu

Dong

et al. 2020

Clin Pharma and Therapeutics

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The unprecedented challenges posed by the coronavirus disease 2019 (COVID-19) pandemic highlight the urgency for applying clinical pharmacology and model-informed drug development in (i) dosage optimization for COVID-19 therapies, (ii) approaching therapeutic dilemmas in clinical trial settings, and (iii) maximizing value of information from impacted non-COVID-19 trials. More than ever, we have a responsibility for adaptive evidence synthesis with a Totality of Evidence mindset in this race against time across biomedical research, clinical practice, drug development, and regulation.

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“…6 7 Moreover, uncertainty still exists on the optimal dosing regimen that would rapidly ensure the adequate therapeutic target concentrations in a drug that is known to have a very long half-life, large distribution into blood and tissues, and slow achievement of the steady-state concentrations, usually within weeks and with wide individual variability. 8 Speculating on a preventive role of HCQ when the drug has been administered chronically is a currently unresolved issue of particular interest for rheumatologists. From our small published case series, three of eight symptomatic patients were taking HCQ, which did not seem to prevent the infection in these cases.…”

mentioning

confidence: 99%

Can hydroxychloroquine protect patients with rheumatic diseases from COVID-19? Response to: ‘Does hydroxychloroquine prevent the transmission of COVID-19?’ by Heldwein and Calado and ‘SLE, hydroxychloroquine and no SLE patients with COVID-19: a comment’ by Joob and Wiwanitkit

Monti

Montecucco

2020

Ann Rheum Dis

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itkit 2 for their interest and comments on our paper. 3 The authors raised the hypothesis that chronic use of hydroxychloroquine (HCQ) for the currently approved indications, such as systemic lupus erythematosus (SLE), could have an impact on the rate of COVID-19 and possibly on the clinical course of the infection.An in vitro antiviral effect of HCQ has been demonstrated on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence suggests that HCQ can interfere with the virus-receptor binding and proliferation, potentially suggesting a prophylactic and therapeutic role of the drug, together with the advantages of its immunomodulatory activity. 4 5 Given the urgent need to identify an efficacious treatment to reduce mortality during the COVID-19 pandemic, HCQ has been included in a number of national protocols and guidelines to treat the infection, based on the results of preliminary clinical data. Nevertheless, the evidence supporting the use of HCQ in vivo is still based on limited evidence. Two open-label, randomised trials with small sample sizes, short follow-up and methodological limitations have led to conflicting results on the efficacy of HCQ in obtaining negative nasopharyngeal swab within 6-7 days from the initiation of treatment. 6 7 Moreover, uncertainty still exists on the optimal dosing regimen that would rapidly ensure the adequate therapeutic target concentrations in a drug that is known to have a very long half-life, large distribution into blood and tissues, and slow achievement of the steady-state concentrations, usually within weeks and with wide individual variability. 8 Speculating on a preventive role of HCQ when the drug has been administered chronically is a currently unresolved issue of particular interest for rheumatologists. From our small published case series, three of eight symptomatic patients were taking HCQ, which did not seem to prevent the infection in these cases. 3 It is still unknown whether the concomitant use of other immunosuppressive drugs might impair the supposed protective role of HCQ. Dr Joob and Wiwanitkit 2 noted how, to date, there have been no reports of patients with SLE affected by COVID-19 in the literature and wondered whether this could be linked to the extensive use of HCQ in this population. However, this may only have been true for the time the authors wrote their correspondence and it might be only a matter of time to learn about SLE patients with COVID-19. Moreover, a recently published paper adds complexity to this scenario and warns on epigenetic dysregulation mechanisms that could lead to an increased risk and severity of SARS-CoV-2 infection in patients with SLE, regardless of the concomitant immunosuppressive medications. Patients with lupus would be characterised by hypomethylation and overexpression of ACE2, which encodes the receptor for SARS-CoV-2 spike glycoprotein, facilitating viral entry and enhancing viraemia. Moreover, oxidative stress induced by viral infections would exacerbate the DNA methylation defect, possibly perpetu...

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Towards Optimization of Hydroxychloroquine Dosing in Intensive Care Unit COVID-19 Patients

Abstract: Abstract Hydroxychloroquine (HCQ) appears to be a promising treatment for COVID-19. However, all ongoing clinical trials with HCQ use different dosing regimens, resulting in various concentrations. Pharmacokinetic studies are therefore needed to define the optimal dosing regimen.

Cited by 87 publications

References 9 publications

Finding the Dose for Hydroxychloroquine Prophylaxis for COVID‐19: The Desperate Search for Effectiveness

Finding the Dose for Hydroxychloroquine Prophylaxis for COVID‐19: The Desperate Search for Effectiveness

Challenges in Drug Development Posed by the COVID‐19 Pandemic: An Opportunity for Clinical Pharmacology

Can hydroxychloroquine protect patients with rheumatic diseases from COVID-19? Response to: ‘Does hydroxychloroquine prevent the transmission of COVID-19?’ by Heldwein and Calado and ‘SLE, hydroxychloroquine and no SLE patients with COVID-19: a comment’ by Joob and Wiwanitkit

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