Effects of bilastine on T-wave morphology and the QTc interval: a randomized, double-blind, placebo-controlled, thorough QTc study

TY - JOUR

T1 - Effects of bilastine on T-wave morphology and the QTc interval

T2 - a randomized, double-blind, placebo-controlled, thorough QTc study

AU - Graff, Claus

AU - Struijk, Johannes J.

AU - Kanters, Jørgen K.

AU - Andersen, Mads Peter

AU - Toft, Egon

AU - Tyl, Benoît

PY - 2012/5/1

Y1 - 2012/5/1

N2 - Background and Objectives: The International Conference of Harmonisation (ICH) E14 guideline for thorough QT studies requires assessing the propensity of new non-antiarrhythmic drugs to affect cardiac repolarization. The present study investigates whether a composite ECG measure of T-wave morphology (Morphology Combination Score [MCS]) can be used together with the heart rate corrected QT interval (QTc) in a fully ICH E14-compliant thorough QT study to exclude clinically relevant repolarization effects of bilastine, a novel antihistamine. Methods: Thirty participants in this crossover study were randomly assigned to receive placebo, moxifloxacin 400 mg, bilastine at therapeutic and supratherapeutic doses (20 and 100 mg) and bilastine 20 mg co-administered with ketoconazole 400 mg. Resting ECGs recorded at 12 nominal time points before and after treatments were used to determine Fridericia corrected QTc (QTcF) and MCS from the T-wave characteristics: asymmetry, flatness and notching. Results: There were no effects of bilastine monotherapy (20 and 100 mg) on MCS or QTcF at those study times where the bilastine plasma concentrations were highest. MCS changes for bilastine monotherapy did not exceed the normal intrasubject variance of T-wave shapes for triplicate ECG recordings. Maximum QTcF prolongation for bilastine monotherapy was 5ms or less: 3.8 ms (90%CI 0.3, 7.3 ms) for bilastine 20 mg and 5.0 ms (90%CI 2.0, 8.0 ms)for bilastine 100 mg. There were no indications of bilastine inducing larger repolarization effects on T-wave morphology as compared with the QTcF interval, as evidenced by the similarity of z-score equivalents for placebocorrected changes in MCS and QTcF values. Conclusion: This study shows that bilastine, at therapeutic and supratherapeutic dosages, does not induce any effects on T-wave morphology or QTcF. These results confirm the absence of an effect for bilastine on cardiac repolarization.

AB - Background and Objectives: The International Conference of Harmonisation (ICH) E14 guideline for thorough QT studies requires assessing the propensity of new non-antiarrhythmic drugs to affect cardiac repolarization. The present study investigates whether a composite ECG measure of T-wave morphology (Morphology Combination Score [MCS]) can be used together with the heart rate corrected QT interval (QTc) in a fully ICH E14-compliant thorough QT study to exclude clinically relevant repolarization effects of bilastine, a novel antihistamine. Methods: Thirty participants in this crossover study were randomly assigned to receive placebo, moxifloxacin 400 mg, bilastine at therapeutic and supratherapeutic doses (20 and 100 mg) and bilastine 20 mg co-administered with ketoconazole 400 mg. Resting ECGs recorded at 12 nominal time points before and after treatments were used to determine Fridericia corrected QTc (QTcF) and MCS from the T-wave characteristics: asymmetry, flatness and notching. Results: There were no effects of bilastine monotherapy (20 and 100 mg) on MCS or QTcF at those study times where the bilastine plasma concentrations were highest. MCS changes for bilastine monotherapy did not exceed the normal intrasubject variance of T-wave shapes for triplicate ECG recordings. Maximum QTcF prolongation for bilastine monotherapy was 5ms or less: 3.8 ms (90%CI 0.3, 7.3 ms) for bilastine 20 mg and 5.0 ms (90%CI 2.0, 8.0 ms)for bilastine 100 mg. There were no indications of bilastine inducing larger repolarization effects on T-wave morphology as compared with the QTcF interval, as evidenced by the similarity of z-score equivalents for placebocorrected changes in MCS and QTcF values. Conclusion: This study shows that bilastine, at therapeutic and supratherapeutic dosages, does not induce any effects on T-wave morphology or QTcF. These results confirm the absence of an effect for bilastine on cardiac repolarization.

KW - Adult

KW - Aza Compounds

KW - Benzimidazoles

KW - Cross-Over Studies

KW - Double-Blind Method

KW - Electrocardiography

KW - Female

KW - Guidelines as Topic

KW - Histamine Antagonists

KW - Humans

KW - Long QT Syndrome

KW - Male

KW - Piperidines

KW - Quinolines

KW - Time Factors

KW - Young Adult

U2 - 10.2165/11599270-000000000-00000

DO - 10.2165/11599270-000000000-00000

M3 - Journal article

C2 - 22393898

SN - 1173-2563

VL - 32

SP - 339

EP - 351

JO - Clinical Drug Investigation

JF - Clinical Drug Investigation

IS - 5

ER -