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Azimilide pharmacokinetics and pharmacodynamics upon multiple oral dosing
Author(s) -
Corey Alfred,
AlKhalidi Hussein,
Brezovic Christopher,
Marcello Stephen,
Parekh Nikhil,
Taylor Kevin,
Karam Roger
Publication year - 1999
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/(sici)1099-081x(199903)20:2<59::aid-bdd155>3.0.co;2-6
Subject(s) - pharmacokinetics , pharmacodynamics , steady state (chemistry) , dosing , medicine , pharmacology , loading dose , anesthesia , chemistry
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 ( E max ) ranged from 24 to 28% change in QT c from baseline. 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. Copyright © 1999 John Wiley & Sons, Ltd.