Azimilide pharmacokinetics and pharmacodynamics upon multiple oral dosing

Abstract

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.

Cumulative Experience of Azimilide-Associated Torsades de Pointes Ventricular Tachycardia in the 19 Clinical Studies Comprising the Azimilide Database

“…One possible explanation is that AF studies required loading (23). Another probable explanation is that the sudden heart rate slowing associated with termination of paroxysms of AF by DC cardioversion in these studies (i.e., conversion to sinus rhythm) may increase the risk for TdP in this population (24).…”

Influence of Coadministration on the Pharmacokinetics of Azimilide Dihydrochloride and Digoxin

“…The effect of azimilide on the QT c interval was similar to that observed in previous studies in which the predicted E max ranged from 23% to 28% change from baseline, while EC 50 ranged from 432 to 566 ng/mL. 20,21 The range of EC 50 was similar to that observed for peak steady-state azimilide blood concentrations achieved with 100 mg/d of azimilide dihydrochloride. 21 The observed prolongation in QT c was slightly less upon coadministration with digoxin.…”

“…20,21 The range of EC 50 was similar to that observed for peak steady-state azimilide blood concentrations achieved with 100 mg/d of azimilide dihydrochloride. 21 The observed prolongation in QT c was slightly less upon coadministration with digoxin. This difference in QT c prolongation appeared to be related to a 2-fold increase in the apparent EC 50 for azimilide when administered with digoxin, with no change in E max .…”

Atrial Fibrillation: Epidemiologic Considerations and Rationale for Conversion and Maintenance of Sinus Rhythm

“…It differs structurally from the methane-sulfonamide-substituted agents, such as sotalol, dofetilide, or ibutilide. Although it is not a benzofuran derivative, in many respects, azimilide resembles amiodarone, which also maintains a class III effect at high stimulation frequencies (71)(72)(73)(74)(75)(76)(77). The terminal half-life of azimilide is 4 to 5 days, it can be administered once daily, and it is eliminated by hepatic metabolism (75).…”