Azimilide pharmacokinetics and pharmacodynamics upon multiple oral dosing

`This study assessed steady-state azimilide pharmacokinetics and pharmacody namics 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 t o 14 days, with 1, 2 or 3 days of loading. Another group of > 55-year-old s ubjects received 100 mg day(-1) with a 3-day loading regimen. There was a s light overshoot of steady-state (24%) after loading, but concentrations dec reased to steady-state by day 7. Mean peak steady-state azimilide concentra tions ranged from 186 to 1030 ng mL(-1) across the 35-200 mg day(-1) dose r ange, while mean trough steady-state azimilide concentrations ranged from 1 08 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. T he mean maximum effect (E-max) ranged from 24 to 28% change in QT(c) from b aseline. The concentration needed to attain one half E-max 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. Copyrig ht (C) 1999 John Wiley & Sons, Ltd.