학술논문
A phase 1 trial of AP30663, a KCa 2 channel inhibitor in development for conversion of atrial fibrillation.
Document Type
Article
Author
Yfanti, Christina; Vestbjerg, Birgitte; van't Westende, Juliette; Edvardsson, Nils; Monfort, Laia Meseguer; Olesen, Morten Salling; Bentzen, Bo Hjorth; Grunnet, Morten; Eveleens Maarse, Boukje C.; Diness, Jonas Goldin; Kemme, Michiel J. B.; Sørensen, Ulrik; Moerland, Matthijs; van Esdonk, Michiel J.; Klaassen, Erica S.; Gal, Pim; Holst, Anders G.
Source
Subject
*INTRAVENOUS therapy
*CONFIDENCE intervals
*CALCIUM ions
*ARRHYTHMIA
*ATRIAL fibrillation
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Language
ISSN
0306-5251
Abstract
Aims: AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca2+ activated K+ (KCa2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first‐in‐human trial. Methods: Sixteen healthy male volunteers were randomized into 2 cohorts: 6‐ and 8‐mg/kg intravenous single‐dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected. Results: AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5–58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7–64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half‐life of around 3 h. Conclusion: AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off‐target inhibition of the IKr channel. [ABSTRACT FROM AUTHOR]