Pharmacokinetic and pharmacodynamic properties of a single intravenous dose of ibutilide fumarate: a phase I, randomized, open-label, increasing-dose study in healthy Chinese men.

BACKGROUND: Atrial flutter is a common sustained atrial tachyarrhythmia whose frequency increases with age. Ibutilide is a class III antiarrhythmic agent used for the cardioversion of atrial flutter or atrial fibrillation.

OBJECTIVE: This study assessed the pharmacokinetic (PK) and pharmacodynamic properties and tolerability of a single intravenous dose of ibutilide fumarate in healthy Chinese men.

METHODS: This Phase I, randomized, open-label, increasing-dose trial was conducted at the Clinical Pharmacology Center, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing, People's Republic of China. Healthy, nonsmoking men aged 18 to 45 years and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 6 treatment groups: ibutilide 0.005, 0.01, or 0.02 mg/kg, or 0.5, 0.75, or 1.0 mg. Each volunteer received a 10-minute infusion of ibutilide under fasting conditions. For analysis of PK properties, blood samples were obtained at the following times: immediately before administration of study drug; 3, 5, 8, 10, 30, and 60 minutes after administration; and 2, 4, 6, 8, 12, and 24 hours after administration. Plasma ibutilide concentrations were determined using a validated high- performance liquid chromatography method with tandem mass-spectrometric detection. Continuous electrocardiographic monitoring was performed, and 12-lead electrocardiograms were recorded before dosing and at defined times from the start of infusion until 24 hours after dosing. Tolerability was assessed throughout the study based on physical examinations, measurement of vital signs, laboratory analyses, and monitoring of adverse effects.

RESULTS: Forty healthy Chinese men were enrolled (mean [SD] age, 24.0 [3.9] years [range, 19-36 years]; mean [SD] body weight, 62.8 [7.9] kg [range, 48- 80 kg]). The plasma ibutilide end-of-infusion concentration and AUC(0-infinity) increased approximately linearly with increasing doses of ibutilide. No statistically significant differences in the principal PK parameters were found among dosage groups; t(1/2) ranged from 7.5 to 9.1 hours, systemic clearance from 68 to 85 mL/min per kg, and Vd from 51 to 60 L/kg. The mean QTc interval was significantly increased during and after ibutilide infusion (baseline range, 406-418 milliseconds; maximum range, 469-683 milliseconds; P < 0.05 vs baseline). The changes in QTc interval were dose dependent, and there was a significant correlation between plasma ibutilide concentrations and changes in the QTc interval (r = 0.7244; P < 0.01). There were no significant changes in blood pressure or the QRS and PR intervals. One volunteer complained of dizziness, but no other apparent adverse effects were observed.

CONCLUSIONS: The results of this study in a selected population of healthy Chinese men suggest that the PK properties of ibutilide are linear with respect to dosing. A single intravenous dose of ibutilide prolonged the QTc interval in a dose- and concentration- dependent manner. Ibutilide was generally well tolerated.