Levocetirizine does not prolong the QT/QTc interval in healthy subjects: results from a thorough QT study.
OBJECTIVE
To conduct a thorough QT study of levocetirizine, a non-sedating antihistamine, in accordance with International Conference on Harmonisation (ICH) E14 guidance.


METHODS
The study was designed as a single-dose, placebo and positive-controlled, four-way crossover, randomised trial in which 52 healthy male and female subjects participated. Levocetirizine (5 and 30 mg) and placebo were administered double-blind, and the positive control, moxifloxacin (400 mg), was open-label. Electrocardiograms (ECGs) were obtained by continuous Holter monitoring at various time points (three per time point) during a 24-h period at baseline and after each treatment. The ECGs were read centrally in a blinded manner. QT intervals were corrected for heart rate using a gender- and study-specific correction (QTcSS) and Fridericia's correction (QTcF). The largest QTc time-matched and baseline-subtracted difference between each active drug and the placebo (largest delta delta QTcSS) was derived from a mixed-effect analysis of variance.


RESULTS
The one-sided 95% upper limits of the largest delta delta QTcSS for levocetirizine were 5.7 ms (5 mg) and 3.9 ms (30 mg), with mean estimates of 2.9 and 1.1 ms, respectively. Similar results were obtained for the delta delta QTcF data. Statistically, moxifloxacin significantly lengthened the QTcSS, with a one-sided 95% lower limit of the largest delta delta QTcSS of 10.5 ms and a mean estimate of 13.4 ms. There was no relationship between the measured delta QTcSS and the plasma concentration of levocetirizine, whereas a statistically significant linear relationship was observed with the plasma concentration of moxifloxacin [slope estimate 0.004 ms/(ng/mL); 95% confidence interval: 0.003-0.005].


CONCLUSIONS
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.
Hulhoven
Réginald
R
Clinical Pharmacology, UCB Pharma SA, Chemin du Foriest 1420, Braine-l'Alleud, Belgium. reginald.hulhoven@ucb-group.com
Rosillon
Dominique
D
Letiexhe
Michel
M
Meeus
Marie-Anne
MA
Daoust
Agnès
A
Stockis
Armel
A
D000293:Adolescent; D000328:Adult; D001372:Aza Compounds / Q000009:adverse effects / Q000493:pharmacokinetics; D017332:Cetirizine / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015716:Electrocardiography, Ambulatory; D005260:Female; D024841:Fluoroquinolones; D006339:Heart Rate; D039563:Histamine H1 Antagonists, Non-Sedating / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics
D001372:Aza Compounds; D024841:Fluoroquinolones; D039563:Histamine H1 Antagonists, Non-Sedating; D010879:Piperazines; D011804:Quinolines; C472067:levocetirizine; D000077266:Moxifloxacin; D017332:Cetirizine