CLINICAL RESEARCH: HEART RHYTHM DISORDERS
The Combined Use of Ibutilide as an Active Control With Intensive Electrocardiographic Sampling and Signal Averaging as a Sensitive Method to Assess the Effects of Tadalafil on the Human QT Interval
Charles M. Beasley, Jr, MD*,*,
Malcolm I. Mitchell, MBBS, MFPM ,
Alex A. Dmitrienko, PhD*,
Jeffrey T. Emmick, MD, PhD*,
Wei Shen, PhD*,
Timothy M. Costigan, PhD*,
Alun W. Bedding, BS,
Michael A. Turik, MD ,
Arash Bakhtyari, MBChB, FRCS ,
Margaret R. Warner, PhD, DVM*,
Jeremy N. Ruskin, MD||,
Louis R. Cantilena, Jr, MD, PhD¶ and
Robert A. Kloner, MD, PhD#
* Lilly Research Laboratories, Indianapolis, Indiana
Lilly Clinic, Windlesham, United Kingdom
Lilly Clinic, Indianapolis, Indiana
Simbec Research Limited, Merthyr Tydfil, United Kingdom
|| Massachusetts General Hospital, Boston, Massachusetts
¶ Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland
# The Heart Institute, Good Samaritan Hospital, Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
Manuscript received June 3, 2004;
revised manuscript received April 28, 2005,
accepted May 3, 2005.
* Reprint requests and correspondence: Dr. Charles M. Beasley, Jr., Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285
(Email: cmbeasleyj{at}lilly.com).
OBJECTIVES: This study was designed to evaluate effects of tadalafil, a phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction (ED), on the QT interval.
BACKGROUND: Cardiovascular disease is common in men with ED. Men with cardiovascular disease and ED may have decreased cardiac repolarization reserve.
METHODS: Effects of tadalafil (100 mg by mouth), ibutilide (0.002 mg/kg intravenously), and placebo on the QT interval in healthy men were compared (placebo and tadalafil [n = 90], with a subset [n = 61] receiving all treatments; mean age 30 years, range 18 to 53 years). Electrocardiographic sampling was done for two days before treatment and on treatment days. The QT was corrected for RR interval with five correction methods, including an individual correction (QTcI). Plasma concentrations of tadalafil were measured to evaluate concentration-QT effect relationships.
RESULTS: At the time corresponding to maximum plasma concentration of tadalafil, the mean difference in the change in QTcI between tadalafil and placebo was 2.8 ms; tadalafil was equivalent to placebo (a priori, upper limit of 90% confidence interval <10 ms [actual = 4.4 ms]; post hoc, upper limit of 95% confidence interval <5 ms [actual = 4.8]). The active control, ibutilide, significantly increased QTcI by 6.9 and 8.9 ms compared with tadalafil and placebo, respectively. Similar statistical results were obtained with four additional QT correction methods. No subject had a QTcI  450 ms or an increase in QTcI 30 ms with any treatment.
CONCLUSIONS: Based on the a priori statistical test of equivalence, placebo and high-dose tadalafil produced equivalent effects on the QT interval. This study reliably discerned 5- to 10-ms changes in corrected QT in the ibutilide active control group.
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Abbreviations and Acronyms
| | CI = confidence interval | | ECG = electrocardiogram | | ED = erectile dysfunction | | HERG = human ether-a-go-go-related gene | | HR = heart rate | | MUSE = Marquette Universal System for Electrocardiography | | PDE5 = phosphodiesterase-5 | | QTc = corrected QT | | QTcB = corrected QT (Bazett corrected) | | QTcI = corrected QT (individual corrected) | | Tmaxh = time of maximum concentration of tadalafil for each subject |
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