No cardiac effects of therapeutic and supratherapeutic doses of rupatadine: results from a 'thorough QT/QTc study' performed according to ICH guidelines.
OBJECTIVE
To evaluate the effects of therapeutic and supratherapeutic doses of rupatadine on cardiac repolarization in line with a 'thorough QT/QTc study' protocol performed according to International Conference on Harmonization guidelines.


METHODS
This was a randomized (gender-balanced), parallel-group study involving 160 healthy volunteers. Rupatadine, 10 and 100 mg day(-1), and placebo were administered single-blind for 5 days, whilst moxifloxacin 400 mg day(-1) was given on days 1 and 5 in open-label fashion. ECGs were recorded over a 23-h period by continuous Holter monitoring at baseline and on treatment days 1 and 5. Three 10-s ECG samples were downloaded at regular intervals and were analysed independently. The primary analysis of QTc was based on individually corrected QT (QTcI). Treatment effects on QTcI were assessed using the largest time-matched mean difference between the drug and placebo (baseline-subtracted) for the QTcI interval. A negative 'thorough QT/QTc study' is one where the main variable is around < or =5 ms, with a one-sided 95% confidence interval that excludes an effect >10 ms.


RESULTS
The validity of the trial was confirmed by the fact that the moxifloxacin-positive control group produced the expected change in QTcI duration (around 5 ms). The ECG data for rupatadine at both 10 and 100 mg showed no signal effects on the ECG, after neither single nor repeated administration. Furthermore, no pharmacokinetic/pharmacodynamic relationship, gender effects or clinically relevant changes in ECG waveform outliers were observed. No deaths or serious or unexpected adverse events were reported.


CONCLUSIONS
This 'thorough QT/QTc study' confirmed previous experience with rupatadine and demonstrated that it had no proarrhythmic potential and raised no concerns regarding its cardiac safety.
Donado
Ester
E
Clinical Development Unit, J Uriach y Compañía, Palau-solità i Plegamans, Spain.
Izquierdo
Iñaki
I
Pérez
Iñaki
I
García
Olga
O
Antonijoan
Rosa M
RM
Gich
Ignaci
I
Solans
Anna
A
Peña
Juana
J
Morganroth
Joel
J
Barbanoj
Manuel J
MJ
D000293:Adolescent; D000328:Adult; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D003533:Cyproheptadine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D013997:Time Factors; D055815:Young Adult
D018926:Anti-Allergic Agents; D039563:Histamine H1 Antagonists, Non-Sedating; D010972:Platelet Activating Factor; C103639:rupatadine; D003533:Cyproheptadine
Neuropsychobiology. 2004;50(4):311-21
15539863
Clin Exp Allergy. 2002 Apr;32(4):489-98
11972592
J Investig Allergol Clin Immunol. 2006;16 Suppl 1:13-23
17357373
Am J Cardiol. 2004 Jun 1;93(11):1378-83, A6
15165918
Clin Pharmacol Ther. 2009 May;85(5):481-4
19225450
Expert Opin Pharmacother. 2006 Oct;7(14):1989-2001
17020424
J Electrocardiol. 2004 Jan;37(1):25-9
15132366
Hum Psychopharmacol. 2007 Jul;22(5):289-97
17599335
Br J Pharmacol. 1999 Nov;128(5):1071-81
10556945
JAMA. 1993 Mar 24-31;269(12):1532-6
8445816
Rev Esp Cardiol. 2009 Mar;62(3):330-1; author reply 332
19268083
Rev Esp Cardiol. 2008 Mar;61(3):328-9
18361911
Allergy. 2008 Apr;63 Suppl 87:5-28
18339040
Eur J Pharmacol. 2006 Dec 28;553(1-3):215-21
17078945
Clin Exp Allergy. 2006 Jan;36(1):5-7
16393259
Hum Psychopharmacol. 2006 Jan;21(1):13-26
16389668
Clin Ther. 2007 May;29(5):900-908
17697908
Eur Heart J. 2000 Aug;21(15):1216-31
10924311
Heart. 2003 Nov;89(11):1363-72
14594906
Drugs Today (Barc). 2003 Jun;39(6):451-68
12944997
J Allergy Clin Immunol. 2001 Nov;108(5 Suppl):S147-334
11707753
Clin Exp Allergy. 2003 Sep;33(9):1305-24
12956754
Eur J Clin Pharmacol. 2007 Nov;63(11):1011-7
17891537