Pharmacokinetics and pharmacodynamics of hydroxychloroquine in hospitalized patients with COVID-19

Zahr, Noël; Urien, Saı̈k; Llopis, B; Pourcher, Valérie; Paccoud, Olivier; Bleibtreu, Alexandre; Mayaux, Julien; Gandjbakhch, Estelle; Hékimian, Guillaume; Benveniste, Olivier; Saadoun, David; Allenbach, Yves; Pinna, Bruno; Cacoub, P.; Funck‐Brentano, Christian; Salem, Joe‐Elie

doi:10.1016/j.therap.2021.01.056

Cited by 10 publications

(13 citation statements)

References 37 publications

(46 reference statements)

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“…To the best of our knowledge, this is the first study investigating C HCQ after a short-term treatment such as those used in SARS-CoV-2 infection during the first pandemic surge. Recent studies have indeed evaluated the short-term treatment with HCQ and have indicated the HCQ doses needed to achieve an effective level against SARS-CoV-2 [ 25 ]; however, no data on drug elimination after treatment discontinuation are available.…”

Section: Discussionmentioning

confidence: 99%

“…We measured C HCQ in whole blood and not in plasma because HCQ accumulates in red blood cells, in which its concentrations are much higher and less variable than in plasma [ 22 ]; moreover, whole blood concentration better represents the amount of drug accumulated within the body’s tissues through time [ 19 , 25 ]. Hydroxychloroquine concentrations were measured during hospitalisation (12 samples) and/or at the follow-up visit (91 samples).…”

Section: Methodsmentioning

confidence: 99%

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Hydroxychloroquine Blood Concentrations Can Be Clinically Relevant Also After Drug Discontinuation

et al. 2022

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Background and Objective Hydroxychloroquine was widely used during the severe acute respiratory syndrome coronavirus 2 pandemic as an antiviral drug. Most previous pharmacokinetic/pharmacodynamic studies on hydroxychloroquine were conducted on healthy volunteers or patients receiving long-term therapy. There are no studies on the elimination of hydroxychloroquine after short-term treatments. Hydroxychloroquine is known to have a pro-arrhythmic effect through QT interval prolongation, but data in this setting are not conclusive. Our aims were to estimate the time needed for hydroxychloroquine concentrations ( C HCQ ) to drop to a safe concentration (500 ng/mL) after a short-term therapeutic cycle and to correlate the corrected QT interval with C HCQ . Methods We collected blood samples and electrocardiograms of patients who underwent short-term therapy with hydroxychloroquine during drug intake and after discontinuation. Hydroxychloroquine concentrations were determined by high-performance liquid chromatography–tandem mass spectrometry and analysed with a linear regression model to estimate the elimination time of the drug after its discontinuation. We conducted a multivariate analysis of the corrected QT interval correlation with C HCQ . Results Our data suggest that short-term hydroxychloroquine courses can generate significant C HCQ persisting above 500 ng/mL up to 16 days after discontinuation of treatment. Corrected QT interval prolongation significantly correlates with C HCQ . Conclusions The study confirms the long half-life of hydroxychloroquine and its effect on the corrected QT interval even after short-term courses of the drug. This can inform the clinician using hydroxychloroquine treatments that it would be safer to start or re-initiate treatments with corrected QT interval-prolonging potential 16 days after hydroxychloroquine discontinuation.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Hydroxychloroquine Blood Concentrations Can Be Clinically Relevant Also After Drug Discontinuation

et al. 2022

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“… 18 , 19 , 23 , 24 Indeed, important differences have been observed between HCQ pharmacokinetic parameters as evidenced recently by its use in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19). 25 Historically, terminal elimination half-lives were considered very long, 40–50 days for HCQ 18 , 23 and up to 60 days for CQ. 19 , 24 More recent studies suggest a shorter half-life of about 5 days.…”

Section: Pharmacology Of Hydroxychloroquinementioning

confidence: 99%

“… 19 , 24 More recent studies suggest a shorter half-life of about 5 days. 25 , 26 A long HCQ half-life can be attributed to extensive tissue uptake rather than to an intrinsic inability to clear the drug. The expected delay in the attainment of steady-state concentrations (3–4 months) may be in part responsible for the slow therapeutic response observed with HCQ.…”

Section: Pharmacology Of Hydroxychloroquinementioning

confidence: 99%

Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge

Dima

Jurcuţ²,

Chasset

et al. 2022

Therapeutic Advances in Musculoskeletal

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The antimalarial hydroxychloroquine (HCQ) has demonstrated several crucial properties for the treatment of systemic lupus erythematosus (SLE). Herein, we reviewed the main HCQ pharmacologic features, detailed its mechanism of action, and summarized the existing guidelines and recommendations for HCQ use in rheumatology with a systematic literature search for the randomized controlled trials focused on lupus. HCQ has been shown to decrease SLE activity, especially in mild and moderate disease, to prevent disease flare and to lower the long-term glucocorticoid need. The numerous benefits of HCQ are extended to pregnancy and breastfeeding period. Based on cohort studies, antithrombotic and metabolic HCQ’s effects were shown, including lipid-lowering properties, which might contribute to an improved cardiovascular risk. Moreover, early HCQ use in antinuclear antibodies positive individuals might delay the progression to SLE. Finally, HCQ has a significant favorable impact on long-term outcomes such as damage accrual and mortality in SLE. Based on these multiple benefits, HCQ is now the mainstay long-term treatment in SLE, recommended by current guidelines in all patients unless contraindications or side effects. The daily dose associated with the best compromise between efficacy and safety is matter of debate. The concern regarding retinal toxicity rather than proper efficacy data is the one that dictated the daily dosage of ⩽5 mg/kg/day actual body weight currently agreed upon.

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“… 22 Recent study showed that pretreatment with HCQ has shown a better effect on antiviral activity, 17 and it has been reported that loading doses of 1600 mg HCQ followed by 600 mg daily doses are needed have a relevant effect to SARS-CoV-2 inhibition within 72 hours in 60% of patients with COVID-19. 23 Finally, a study where the antiviral mechanisms of CQ and adverse effects were evaluated showed that the use of CQ as a prophylactic treatment was more effective than when it is used as a therapeutic treatment. 24 However, CQ and HCQ have been reported to have various adverse effects, the CQ being the most toxic in overdose.…”

Section: Introductionmentioning

confidence: 99%

New prophylaxis regimen for SARS-CoV-2 infection in health professionals with low doses of hydroxychloroquine and bromhexine: a randomised, double-blind placebo clinical trial (ELEVATE Trial)

et al. 2021

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IntroductionSARS-CoV-2 infection in Mexico has caused ~2.7 million confirmed cases; around 20%–25% of health workers will be infected by the virus at their workplace, with approximately 4.4% of mortality. High infectivity of SARS-CoV-2 is related with cell entry mechanism, through the ACE receptor. SARS-CoV-2 requires transmembrane protease serine 2 to cleave its spike glycoprotein and ensure fusion of host cell and virus membrane. We propose studying prophylactic treatment with hydroxychloroquine (HCQ) and bromhexine (BHH), which have been shown to be effective in preventing SARS-CoV-2 infection progression when administered in early stages. The aim of this study is to assess the efficacy of HCQ and BHH as prophylactic treatments for SARS-CoV-2 infection in healthy health workers exposed to the virus.Methods and analysisDouble-blind randomised clinical trial, with parallel allocation at a 1:1 ratio with placebo, of low doses of HCQ plus BHH, for 60 days. Study groups will be defined as follows: (1) HCQ 200 mg/day+BHH 8 mg/8 hours versus (2) HCQ placebo plus BHH placebo. Primary endpoint will be efficacy of both interventions for the prevention of SARS-CoV-2 infection, determined by the risk ratio of infected personnel and the absolute risk. At least a 16% reduction in absolute risk is expected between the intervention and placebo groups; a minimum of 20% infection is expected in the placebo group. The sample size calculation estimated a total of 214 patients assigned: two groups of 107 participants each.Ethics and disseminationThis protocol has been approved by the local Medical Ethics Committee (National Institute of Rehabilitation ‘Luis Guillermo Ibarra Ibarra’, approval number INRLGII/25/20) and by the Federal Commission for Protection against Sanitary Risks (COFEPRIS, approval number 203 300 410A0058/2020). The results of the study will be submitted for publication in peer-reviewed journals and disseminated through conferences.Trial registration numberNCT04340349.

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Pharmacokinetics and pharmacodynamics of hydroxychloroquine in hospitalized patients with COVID-19

Cited by 10 publications

References 37 publications

Hydroxychloroquine Blood Concentrations Can Be Clinically Relevant Also After Drug Discontinuation

Hydroxychloroquine Blood Concentrations Can Be Clinically Relevant Also After Drug Discontinuation

Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge

New prophylaxis regimen for SARS-CoV-2 infection in health professionals with low doses of hydroxychloroquine and bromhexine: a randomised, double-blind placebo clinical trial (ELEVATE Trial)

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