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.

N1 - Publisher Copyright: © 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

PY - 2024

Y1 - 2024

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.

KW - atrial fibrillation

KW - Ca activated K (K2) channel

KW - QT interval

UR - http://www.scopus.com/inward/record.url?scp=85181680564&partnerID=8YFLogxK

U2 - 10.1111/bcp.15973

DO - 10.1111/bcp.15973

M3 - Journal article

C2 - 37990600

AN - SCOPUS:85181680564

JO - British Journal of Clinical Pharmacology, Supplement

JF - British Journal of Clinical Pharmacology, Supplement

SN - 0264-3774

ER -