Azimilide pharmacokinetics and pharmacodynamics upon multiple oral dosing

• Published in: Biopharmaceutics & drug disposition Vol. 20; no. 2; pp. 59 - 68
• Main Authors: Corey, Alfred, Al-Khalidi, Hussein, Brezovic, Christopher, Marcello, Stephen, Parekh, Nikhil, Taylor, Kevin, Karam, Roger
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.03.1999; Wiley
• Subjects: Administration, Oral; Adolescent; Adult; Anti-Arrhythmia Agents - administration & dosage; Anti-Arrhythmia Agents - pharmacokinetics; Anti-Arrhythmia Agents - pharmacology; Antiarythmic agents; azimilide; Biological and medical sciences; Cardiovascular system; class III antiarrhythmic; Drug Administration Schedule; Female; Humans; Hydantoins; Imidazoles - administration & dosage; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Imidazolidines; Male; Medical sciences; multiple dosing; pharmacodynamics; pharmacokinetics; Pharmacology. Drug treatments; Piperazines - administration & dosage; Piperazines - pharmacokinetics; Piperazines - pharmacology; Multiple dose; Human; QT interval; Azimilide; Activity concentration relation; Oral administration; Electrocardiography; Antiarrhythmic agent; Normal; Pharmacokinetics; Dose activity relation
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/(SICI)1099-081X(199903)20:2<59::AID-BDD155>3.0.CO;2-6

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. Copyright © 1999 John Wiley & Sons, Ltd.