Effect of hydroxychloroquine on the cardiac ventricular repolarization: A randomized clinical trial

Maarse, Boukje C Eveleens; Graff, Claus; Kanters, Jørgen K.; Esdonk, Michiel J. van; Kemme, Michiel J. B.; Veld, Aliede E. in ‘t; Jansen, Manon A. A.; Moerland, Matthijs; Gal, Pim

doi:10.1111/bcp.15013

Cited by 5 publications

(6 citation statements)

References 55 publications

(123 reference statements)

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“…These findings are similar to previous findings such as those recently reported by Eveleens Maarse et al who, in a randomized controlled trial in healthy volunteers, did not find an effect at plasma concentrations up to 200 ng/ mL. 27 The use of sex-specific reference ranges for QTc might have revealed additional information but for our current analysis a reference range for QTc of <500 ms was used for all patients.…”

Section: Discussionsupporting

confidence: 92%

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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Section: Discussionsupporting

confidence: 92%

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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“…The cardiovascular effects linked to antimalarials are mainly those that compromise the cardiac conduction system followed by the ones that alter anatomy (Desmarais et al, 2021;Eveleens Maarse et al, 2022). In this regard, none of our patients presented adverse cardiovascular effects during the study period.…”

Section: Pharmacological Treatment and Adverse Eventsmentioning

confidence: 66%

Adverse events in rheumatoid arthritis patients under antimalarial treatment—Is there cardiovascular compromise?

Santos-Moreno¹,

Ibatá²,

Martínez³

et al. 2023

Front. Drug Saf. Regul.

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Introduction: The antimalarials chloroquine and hydroxychloroquine have been used for several decades in treating malaria and some autoimmune diseases—mainly rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)—with excellent efficacy and safety. Due to the massive use of antimalarials worldwide for managing SARS-CoV-2/COVID-19 infection during the last 2 years and the consequent increase in cardiac arrhythmia, fear has risen about the safety of using antimalarials, especially for patients with increased cardiovascular risk.Objective: To describe a real-life experience about the safety of antimalarials in the setting of a single rheumatological center in Colombia.Methods: This is a cross sectional study that includes patients diagnosed with RA and treated with antimalarials between 2020 and 2021. Clinical follow-up information was gathered from the medical records, and all reported adverse events were described.Results: A total of 957 patients were included, primarily women (79.2%). The most frequent comorbidities were hypertension and osteoporosis. Chloroquine use was more frequent than hydroxychloroquine (86.4% vs. 13.6%). During the observation period, 243 (25.4%) patients presented at least one adverse event, 72 (29.6%) had retinal toxicity, 85 (35%) dermatological events, and 81 (33.3%) gastrointestinal intolerance. Other adverse events reported less frequently (15.2%) included headache, dizziness, lipothymia, and elevated transaminases. There were no reports of cardiovascular events from the period of antimalarial use to the date of data collection despite the high frequency of previous metabolic or cardiovascular disease in this cohort.Conclusion: This study reasserts the evidence of antimalarials safety profile for patients with rheumatological conditions such as RA. RA patients that were treated with antimalarials at doses recommended by the guidelines had no cardiovascular events.

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“…Gastrointestinal complaints (20%) and dizziness (15%) were the most frequently reported adverse events in the active group. There were no findings of clinical concern following assessments of urinalysis, hematology and chemistry laboratory tests, vital signs, physical examination, and ECGs [ 22 ].…”

Section: Resultsmentioning

confidence: 99%

“…4 A. Individual concentration profiles have been published previously [ 22 ]. There were no significant differences in HCQ exposures between age groups (Fig.…”

Section: Resultsmentioning

confidence: 99%

Immunosuppression by hydroxychloroquine: mechanistic proof in in vitro experiments but limited systemic activity in a randomized placebo-controlled clinical pharmacology study

et al. 2023

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Based on its wide range of immunosuppressive properties, hydroxychloroquine (HCQ) is used for the treatment of several autoimmune diseases. Limited literature is available on the relationship between HCQ concentration and its immunosuppressive effect. To gain insight in this relationship, we performed in vitro experiments in human PBMCs and explored the effect of HCQ on T and B cell proliferation and Toll-like receptor (TLR)3/TLR7/TLR9/RIG-I-induced cytokine production. In a placebo-controlled clinical study, these same endpoints were evaluated in healthy volunteers that were treated with a cumulative dose of 2400 mg HCQ over 5 days. In vitro, HCQ inhibited TLR responses with IC50s > 100 ng/mL and reaching 100% inhibition. In the clinical study, maximal HCQ plasma concentrations ranged from 75 to 200 ng/mL. No ex vivo HCQ effects were found on RIG-I-mediated cytokine release, but there was significant suppression of TLR7 responses and mild suppression of TLR3 and TLR9 responses. Moreover, HCQ treatment did not affect B cell and T cell proliferation. These investigations show that HCQ has clear immunosuppressive effects on human PBMCs, but the effective concentrations exceed the circulating HCQ concentrations under conventional clinical use. Of note, based on HCQ’s physicochemical properties, tissue drug concentrations may be higher, potentially resulting in significant local immunosuppression. This trial is registered in the International Clinical Trials Registry Platform (ICTRP) under study number NL8726.

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Effect of hydroxychloroquine on the cardiac ventricular repolarization: A randomized clinical trial

Cited by 5 publications

References 55 publications

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

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

Adverse events in rheumatoid arthritis patients under antimalarial treatment—Is there cardiovascular compromise?

Immunosuppression by hydroxychloroquine: mechanistic proof in in vitro experiments but limited systemic activity in a randomized placebo-controlled clinical pharmacology study

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