Azimilide pharmacokinetics and pharmacodynamics upon multiple oral dosing.
This study assessed steady-state azimilide pharmacokinetics and pharmacodynamics in 119 healthy male and female volunteers. Parallel groups of 18-40-year-old subjects received doses of 35, 100, 150 or 200 mg day(-1) for up to 14 days, with 1, 2 or 3 days of loading. Another group of > 55-year-old subjects received 100 mg day(-1) with a 3-day loading regimen. There was a slight overshoot of steady-state (24%) after loading, but concentrations decreased to steady-state by day 7. Mean peak steady-state azimilide concentrations ranged from 186 to 1030 ng mL(-1) across the 35-200 mg day(-1) dose range, while mean trough steady-state azimilide concentrations ranged from 108 to 549 ng mL(-1). Azimilide pharmacokinetics were proportional to dose, except for renal clearance, and did not differ between 18-40-year-old and > 55-year-old subjects. Pharmacodynamics did not differ across dose groups. The mean maximum effect (Emax) ranged from 24 to 28% change in QTc from baseline. The concentration needed to attain one half Emax ranged from 432 to 542 ng mL(-1) across dose groups. Equilibration was rapid between blood and the biophase, with equilibration half-lives of less than 1 min.
Corey
A
A
Clinical Pharmacology and Pharmacokinetics Department, Proctor and Gamble Pharmaceuticals, Inc., Cincinnati, OH 45242, USA. alfredc@mocr.oapi.com
Al-Khalidi
H
H
Brezovic
C
C
Marcello
S
S
Parekh
N
N
Taylor
K
K
Karam
R
R
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006827:Hydantoins; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D048289:Imidazolidines; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010879:Piperazines; C086123:azimilide