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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

View larger version (31K): [in a new window]   Figure 1 Subject disposition. Subjects were assigned by random allocation to receive one of two sequences of treatment, either a two-way crossover (placebo, tadalafil) or a three-way crossover (placebo, tadalafil, ibutilide). The number of subjects assigned to each sequence of treatments (placebo-tadalafil, n = 32; placebo-tadalafil-ibutilide, n = 67) was sufficient to achieve the total number of subjects treated with both drugs for the three statistical drug pair comparisons specified by the prospective statistical analysis plan (total receiving: placebo vs. tadalafil = 90; tadalafil vs. ibutilide = 62; placebo vs. ibutilide = 61). Reasons for discontinuation are listed in the Results section. One subject received treatment with ibutilide and two treatments with placebo (rather than treatment with tadalafil and placebo). This subject was included in the intent-to-treat ibutilide-placebo, tadalafil-placebo, and tadalafil-ibutilide comparative analyses. *Not included in any of the comparative analyses because subjects did not receive at least two treatments.

View larger version (23K): [in a new window]   Figure 2 Study design and times of electrocardiogram (ECG) recording. At each time point indicated by an X, a 12-lead ECG was recorded for 10 s at 1-min intervals for 10 min (total of 10 ECGs recorded at each time point). For ibutilide treatment days (bottom panel), at each time point indicated by a filled circle, a single 12-lead ECG was recorded for 10 s. Administration of oral tadalafil and placebo was double blind and administration of intravenous ibutilide was unblinded. x = 10 ECGs obtained at 1-min intervals; • = single ECG.

View larger version (46K): [in a new window]   Figure 3 Change (tadalafil minus placebo) in the individually corrected QT interval (QTcI) versus plasma concentration of tadalafil and tadalafil methylcatechol glucuronide.