Pharmacokinetics of ibutilide in patients with heart failure due to left ventricular systolic dysfunction

James E. Tisdale, Brian R. Overholser, Kevin M. Sowinski, Heather A. Wroblewski, Kwadwo Amankwa, Steven Borzak, Joanna R. Kingery, Rita Coram, Douglas P. Zipes, David A. Flockhart, Richard J. Kovacs

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Study 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. Design. Multicenter, prospective pharmacokinetic study. Setting. Four academic medical centers in the United States. Patients. 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. Intervention. 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. Measurements and Main 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] μg/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 μg·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). Conclusion. 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.

Original languageEnglish (US)
Pages (from-to)1461-1470
Number of pages10
JournalPharmacotherapy
Volume28
Issue number12
DOIs
StatePublished - Dec 2008

Fingerprint

Left Ventricular Dysfunction
Heart Failure
Pharmacokinetics
Torsades de Pointes
Stroke Volume
Serum
ibutilide
Atrial Flutter
Indwelling Catheters
Left Ventricular Function
Atrial Fibrillation
Half-Life
Mass Spectrometry
High Pressure Liquid Chromatography
Prospective Studies

Keywords

  • Arrhythmias
  • Heart failure
  • Ibutilide
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Tisdale, J. E., Overholser, B. R., Sowinski, K. M., Wroblewski, H. A., Amankwa, K., Borzak, S., ... Kovacs, R. J. (2008). Pharmacokinetics of ibutilide in patients with heart failure due to left ventricular systolic dysfunction. Pharmacotherapy, 28(12), 1461-1470. https://doi.org/10.1592/phco.28.12.1461

Pharmacokinetics of ibutilide in patients with heart failure due to left ventricular systolic dysfunction. / Tisdale, James E.; Overholser, Brian R.; Sowinski, Kevin M.; Wroblewski, Heather A.; Amankwa, Kwadwo; Borzak, Steven; Kingery, Joanna R.; Coram, Rita; Zipes, Douglas P.; Flockhart, David A.; Kovacs, Richard J.

In: Pharmacotherapy, Vol. 28, No. 12, 12.2008, p. 1461-1470.

Research output: Contribution to journalArticle

Tisdale, JE, Overholser, BR, Sowinski, KM, Wroblewski, HA, Amankwa, K, Borzak, S, Kingery, JR, Coram, R, Zipes, DP, Flockhart, DA & Kovacs, RJ 2008, 'Pharmacokinetics of ibutilide in patients with heart failure due to left ventricular systolic dysfunction', Pharmacotherapy, vol. 28, no. 12, pp. 1461-1470. https://doi.org/10.1592/phco.28.12.1461
Tisdale JE, Overholser BR, Sowinski KM, Wroblewski HA, Amankwa K, Borzak S et al. Pharmacokinetics of ibutilide in patients with heart failure due to left ventricular systolic dysfunction. Pharmacotherapy. 2008 Dec;28(12):1461-1470. https://doi.org/10.1592/phco.28.12.1461
Tisdale, James E. ; Overholser, Brian R. ; Sowinski, Kevin M. ; Wroblewski, Heather A. ; Amankwa, Kwadwo ; Borzak, Steven ; Kingery, Joanna R. ; Coram, Rita ; Zipes, Douglas P. ; Flockhart, David A. ; Kovacs, Richard J. / Pharmacokinetics of ibutilide in patients with heart failure due to left ventricular systolic dysfunction. In: Pharmacotherapy. 2008 ; Vol. 28, No. 12. pp. 1461-1470.
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abstract = "Study 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. Design. Multicenter, prospective pharmacokinetic study. Setting. Four academic medical centers in the United States. Patients. 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. Intervention. 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. Measurements and Main 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] μg/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 μg·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). Conclusion. 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.",
keywords = "Arrhythmias, Heart failure, Ibutilide, Pharmacokinetics",
author = "Tisdale, {James E.} and Overholser, {Brian R.} and Sowinski, {Kevin M.} and Wroblewski, {Heather A.} and Kwadwo Amankwa and Steven Borzak and Kingery, {Joanna R.} and Rita Coram and Zipes, {Douglas P.} and Flockhart, {David A.} and Kovacs, {Richard J.}",
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T1 - Pharmacokinetics of ibutilide in patients with heart failure due to left ventricular systolic dysfunction

AU - Tisdale, James E.

AU - Overholser, Brian R.

AU - Sowinski, Kevin M.

AU - Wroblewski, Heather A.

AU - Amankwa, Kwadwo

AU - Borzak, Steven

AU - Kingery, Joanna R.

AU - Coram, Rita

AU - Zipes, Douglas P.

AU - Flockhart, David A.

AU - Kovacs, Richard J.

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N2 - Study 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. Design. Multicenter, prospective pharmacokinetic study. Setting. Four academic medical centers in the United States. Patients. 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. Intervention. 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. Measurements and Main 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] μg/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 μg·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). Conclusion. 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.

AB - Study 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. Design. Multicenter, prospective pharmacokinetic study. Setting. Four academic medical centers in the United States. Patients. 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. Intervention. 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. Measurements and Main 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] μg/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 μg·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). Conclusion. 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.

KW - Arrhythmias

KW - Heart failure

KW - Ibutilide

KW - Pharmacokinetics

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