Pharmacokinetics of intravenous amiodarone and its electrocardiographic effects on healthy Japanese subjects.
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 (AUC(0-96)) 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 AUC(0-96) 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.
Department of Cardiology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan. mshiga@hij.twmu.ac.jp
Tsuyoshi
T
Shiga
Takanori
T
Tanaka
Shin
S
Irie
Nobuhisa
N
Hagiwara
Hiroshi
H
Kasanuki
D000328:Adult; D000638:Amiodarone / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People; D001711:Biotransformation; D001794:Blood Pressure / Q000187:drug effects*; D003198:Computer Simulation; D015716:Electrocardiography, Ambulatory; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D007564:Japan; D008297:Male; D008954:Models, Biological; D055815:Young Adult
D000889:Anti-Arrhythmia Agents; C036116:desethylamiodarone; D000638:Amiodarone