TY - JOUR
T1 - A phase 1 trial of AP30663, a KCa2 channel inhibitor in development for conversion of atrial fibrillation
AU - Yfanti, Christina
AU - Vestbjerg, Birgitte
AU - van't Westende, Juliette
AU - Edvardsson, Nils
AU - Monfort, Laia Meseguer
AU - Olesen, Morten Salling
AU - Bentzen, Bo Hjorth
AU - Grunnet, Morten
AU - Eveleens Maarse, Boukje C.
AU - Diness, Jonas Goldin
AU - Kemme, Michiel J. B.
AU - Sørensen, Ulrik
AU - Moerland, Matthijs
AU - van Esdonk, Michiel J.
AU - Klaassen, Erica S.
AU - Gal, Pim
AU - Holst, Anders G.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85181680564&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/37990600
U2 - https://doi.org/10.1111/bcp.15973
DO - https://doi.org/10.1111/bcp.15973
M3 - Article
C2 - 37990600
SN - 0306-5251
JO - British journal of clinical pharmacology
JF - British journal of clinical pharmacology
ER -