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Pharmacokinetics of intravenous amiodarone and its electrocardiographic effects on healthy Japanese subjects

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Abstract

The aim of this phase I, dose-escalating study was to evaluate the pharmacokinetics, electrocardiographic effect and safety of amiodarone after a single intravenous administration in Japanese subjects. Thirty-two healthy Japanese male volunteers (20–32 years) were randomized to three single-dose groups (1.25, 2.5 and 5.0 mg/kg). In each group, six (1.25 mg/kg) or ten (2.5 and 5.0 mg/kg) subjects received a single 15-min infusion of intravenous amiodarone, and two subjects received glucose solution as control. The pharmacokinetic profile, blood pressure and electrocardiographic analyses were obtained on a timely basis after up to 77 days. The maximum plasma concentration (C max) and area under the concentration-time curve (AUC0–96) for amiodarone 1.25, 2.5 and 5.0 mg/kg displayed dose-dependent characteristics: mean C max was 2,920 ± 610, 7,140 ± 1,480 and 13,660 ± 3,410 ng/ml, respectively; the mean AUC0-96 was 3,600 ± 700, 8,100 ± 1,600 and 16,600 ± 4,300 ng h/ml, respectively. A long serum half-life (>14 days) was observed for amiodarone and desethylamiodarone. PR intervals were prolonged at 15 min (0.16 ± 0.0.1 vs. 0.15 ± 0.01 s, p = 0.03) and 18 min (0.17 ± 0.01 vs. 0.15 ± 0.01 s, p = 0.03) with the 5.0 mg/kg dose compared with baseline. No other significant changes in electrocardiographic parameters, pulse rate or blood pressure were observed. A needle-pain-induced vasovagal effect appeared in a volunteer, and three volunteers experienced pain at the drug infusion site. After a single infusion of amiodarone at doses of 1.25–5.0 mg/kg, serum concentrations increased in a dose-dependent manner. A single intravenous amiodarone dose barely affected the electrocardiographic parameters and was well tolerated.

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Acknowledgments

The authors thank Stephanie Blick and Nicola Van Aardt of Wolters Kluwer Health Medical Communications, who provided assistance with the preparation of the manuscript. This study was supported by Taisho-Sanofi Synthelabo Co., Ltd. (Sanofi-Aventis KK, Tokyo, Japan).

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Correspondence to Tsuyoshi Shiga.

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This article is based on research that was first reported in Japanese by Shiga et al. Progress in Medicine (2008) 28(Suppl 1):667–670.

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Shiga, T., Tanaka, T., Irie, S. et al. Pharmacokinetics of intravenous amiodarone and its electrocardiographic effects on healthy Japanese subjects. Heart Vessels 26, 274–281 (2011). https://doi.org/10.1007/s00380-010-0047-7

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  • DOI: https://doi.org/10.1007/s00380-010-0047-7

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