Levocetirizine does not prolong the QT/QTc interval in healthy subjects: results from a thorough QT study

Hulhoven, R.; Rosillon, Dominique; Letiexhe, Michel; Meeus, Marie-Anne; Daoust, Agnès; Stockis, Armel

doi:10.1007/s00228-007-0366-5

Cited by 67 publications

(49 citation statements)

References 25 publications

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“…H 1 -antihistamines that fail this scrutiny are not approved for use (Table IV). 1,18,124,125 Long-term safety of the second-generation H 1 -antihistamines cetirizine, desloratadine, fexofenadine, levocetirizine, and loratadine has been documented in randomized controlled trials lasting 6 to 18 months in adults and in children as young as 1 to 2 years old. 1,18,126 Lack of toxicity after overdose.…”

Section: Second (New)-generation H 1 -Antihistaminesmentioning

confidence: 99%

Histamine and H1-antihistamines: Celebrating a century of progress

Simons

2011

Journal of Allergy and Clinical Immunology

453

373

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Section: Second (New)-generation H 1 -Antihistaminesmentioning

confidence: 99%

Histamine and H1-antihistamines: Celebrating a century of progress

Simons

2011

Journal of Allergy and Clinical Immunology

453

373

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“…Five 'QTpositive' drugs were administered at doses intended to cause QTc prolongation of around 9-12 ms on day 1 and 15-20 ms on day 2: (1) oral ondansetron 52 mg and intravenous ondansetron 32 mg [28]; (2) quinine 648 mg three times daily for four doses [29,30]; (3) oral dolasetron 100 mg and intravenous dolasetron 150 mg [31]; (4) oral moxifloxacin 400 mg and intravenous moxifloxacin 800 mg [32,33]; and (5) oral dofetilide 0.125 and 0.25 mg [34]. One negative drug, levocetirizine, was added at the same doses as in its TQT study, 5 and 30 mg [35,36]. An incomplete block design resulted in each study drug being administered to nine subjects and placebo to six subjects in separate periods.…”

Section: The Iq-csrc Prospective Studymentioning

confidence: 99%

Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

et al. 2015

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Exposure-response (ER) analysis has evolved as an important tool to evaluate the effect of a drug on cardiac repolarization, as reflected in the QTc interval. It has been suggested that careful electrocardiogram (ECG) evaluation in 'first-in-human' studies using ER analysis could replace or serve as an alternative to the E14 'thorough QT' study. This commentary shares and discusses the results of a recently conducted study with the objective to evaluate this approach. Six drugs with a well-characterized QT effect, five of which are known QT prolongers, were evaluated in a study design similar to a conventional single-ascending-dose study. Each drug was given to nine healthy subjects (six for placebo) in two dose levels, which for the positive drugs (ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide) were chosen with the intent to cause 10-12 ms and 15-20 ms QTc prolongation. Replicate 12-lead ECGs were extracted from continuous recordings pre-dose and serially after dosing and paired with drug concentration determinations. The ER criteria for the identification of a QT effect, a statistically significant positive ER slope and an effect above 10 ms, were met with all five positive drugs, and an effect exceeding 10 ms could be excluded at the supratherapeutic dose of the negative drug, levocetirizine. The study results thereby provided evidence to support that careful QT assessment in early phase clinical studies can be used as an alternative to the thorough QT study. Clinical and regulatory implications, as well as limitations of this approach, are discussed in the commentary.

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“…In addition, some first-generation H 1 -antihistamines, such as promethazine,[63] brompheniramine,[64] and diphenhydramine,[65] may also be associated with a prolonged QTc and cardiac arrhythmias when taken in large doses or overdoses. No clinically significant cardiac effects have been reported for the second-generation H 1 -antihistamines loratadine, fexofenadine, mizolastine, ebastine, azelastine, cetirizine, desloratadine, and levocetirizine[66-69]. …”

Section: Second-generation H1-antihistaminesmentioning

confidence: 99%

Pharmacology of Antihistamines

Church¹,

Church²

2011

World Allergy Organization Journal

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This article reviews the molecular biology of the interaction of histamine with its H1-receptor and describes the concept that H1-antihistamines are not receptor antagonists but are inverse agonists i.e. they produce the opposite effect on the receptor to histamine. It then discourages the use of first-generation H1-antihistamines in clinical practice today for two main reasons. First, they are less effective than second generation H1-antihistamines. Second, they have unwanted side effects, particularly central nervous system and anti-cholinergic effects, and have the potential for causing severe toxic reactions which are not shared by second-generation H1-antihistamines. There are many efficacious and safe second-generation H1-antihistamines on the market for the treatment of allergic disease. Of the three drugs highlighted in this review, levocetirizine and fexofenadine are the most efficacious in humans in vivo. However, levocetirizine may cause somnolence in susceptible individuals while fexofenadine has a relatively short duration of action requiring twice daily administration for full all round daily protection. While desloratadine is less efficacious, it has the advantages of rarely causing somnolence and having a long duration of action. Lastly, all H1-antihistamines have anti-inflammatory effects but it requires regular daily dosing rather than dosing 'on-demand' for this effect to be clinically demonstrable.

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Levocetirizine does not prolong the QT/QTc interval in healthy subjects: results from a thorough QT study

Abstract: Overall, the results of this thorough QT study indicate that the methodology of the trial was valid and sensitive enough to demonstrate the absence of effect of levocetirizine at both therapeutic (5 mg) and supra-therapeutic (30 mg) doses on cardiac repolarisation.

Cited by 67 publications

References 25 publications

Histamine and H1-antihistamines: Celebrating a century of progress

Histamine and H1-antihistamines: Celebrating a century of progress

Implications of the IQ-CSRC Prospective Study: Time to Revise ICH E14

Pharmacology of Antihistamines

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