Pharmacokinetics of ibutilide in patients with heart failure due to left ventricular systolic dysfunction.
OBJECTIVE
To assess whether the increased risk of ibutilide-induced torsade de pointes in patients with heart failure may be due to increased ibutilide exposure, we sought to determine if the pharmacokinetics of ibutilide are altered in patients with heart failure due to left ventricular systolic dysfunction.


METHODS
Multicenter, prospective pharmacokinetic study.


METHODS
Four academic medical centers in the United States.


METHODS
Sixteen adult patients with atrial fibrillation or atrial flutter requiring conversion to normal sinus rhythm: six patients who had New York Heart Association (NYHA) class II or III heart failure due to left ventricular dysfunction (mean +/- SD left ventricular ejection fraction [LVEF] 30 +/- 9%); 10 patients who did not have left ventricular dysfunction (mean +/- SD LVEF 54 +/- 5% in six of these 10 patients) served as controls.


METHODS
All patients received a single dose of ibutilide 1.0 mg administered intravenously over 10 minutes. Blood samples were obtained through an indwelling catheter in the contralateral arm before ibutilide administration, at the end of the infusion, and at 5, 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, and 48 hours after the infusion.


RESULTS
Serum ibutilide concentrations were determined by using high-performance liquid chromatography and mass spectrometry. No significant differences were noted between the heart failure and normal left ventricular function groups in the following parameters: maximum serum ibutilide concentration (median [interquartile range] 3.8 [2.3-5.7] vs 5.8 [3.1-14.4] microg/L, p=0.31), area under the serum concentration-time curve from time zero extrapolated to infinity (mean +/- SD 11.0 +/- 9.4 vs 13.2 +/- 10.6 microg*hr/L, p=0.88), steady-state volume of distribution (1380 +/- 334 vs 1390 +/- 964 L, p=0.99), systemic clearance (129 +/- 60 vs 125 +/- 81 L/hr, p=0.92), or half-life (12.5 +/- 10.7 vs 12.4 +/- 8.6 hrs, p=0.99).


CONCLUSIONS
The pharmacokinetics of ibutilide do not appear to be altered in patients with NYHA class II or III heart failure due to left ventricular systolic dysfunction. Therefore, the increased risk of ibutilide-induced torsade de pointes in patients with heart failure does not appear to be due to increased ibutilide exposure.
Tisdale
James E
JE
Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Purdue University, 1001 W 10th Street, Indianapolis, IN, USA. jtisdale@iupui.edu
Overholser
Brian R
BR
Sowinski
Kevin M
KM
Wroblewski
Heather A
HA
Amankwa
Kwadwo
K
Borzak
Steven
S
Kingery
Joanna R
JR
Coram
Rita
R
Zipes
Douglas P
DP
Flockhart
David A
DA
Kovacs
Richard J
RJ
D000328:Adult; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D002408:Catheters, Indwelling; D004562:Electrocardiography / Q000379:methods; D006207:Half-Life; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009010:Monte Carlo Method; D011446:Prospective Studies; D012075:Remission, Spontaneous; D012720:Severity of Illness Index; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013610:Tachycardia / Q000139:chemically induced; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*
D000889:Anti-Arrhythmia Agents; D013449:Sulfonamides; C067192:ibutilide