Prospective pharmacokinetically based development of effective infusion regimens for ACC-9358, a new antiarrhythmic drug.
In this study we evaluated the clinical pharmacology of intravenous ACC-9358, a new antiarrhythmic drug derived from a Chinese herbal remedy. In a first-study phase, 0.125 to 1.0 mg/kg during 10 minutes was administered to six patients with chronic nonsustained ventricular arrhythmias. These data were then used to design 3-hour infusions to maintain stable plasma concentrations: these infusions suppressed arrhythmias by 90% or greater for 2 1/2 hours or more at plasma concentrations of 114 to 1010 ng/ml (mean, 400 +/- 421 ng/ml [SD]), and with QRS interval increases of 2.5% to 8.8% (5.1% +/- 2.9%). Mean clearance was 478 +/- 151 ml/min, and elimination half-life was 19.1 +/- 6.1 hours. ACC-9358 did not produce adverse effects in this study. ACC-9358 shows antiarrhythmic activity in humans at concentrations that prolong QRS only slightly and do not alter rate-corrected QT; further studies in other patient populations, at dosages and plasma concentrations defined here, are required to establish a clinical role for ACC-9358. The pharmacokinetically based dose-ranging approach allowed the safe initial evaluation of ACC-9358 in patients.
Pavlou
H N
HN
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.
Funck-Brentano
C
C
Lineberry
M D
MD
Woosley
R L
RL
Roden
D M
DM
D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors; D016276:Ventricular Function / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D011759:Pyrrolidines; C048492:4-hydroxy-N-phenyl-3,5-bis(1-pyrrolidinylmethyl)benzamide