First Clinical Study with AP30663 ‐ a KCa2 Channel Inhibitor in Development for Conversion of Atrial Fibrillation

Autor: Kirsten R. Bergmann, Michiel J. B. Kemme, Ulrik Svane Sørensen, Morten Grunnet, Erica S. Klaassen, Jacobus Burggraaf, Nils Edvardsson, Mahdi Saghari, Bo Hjorth Bentzen, Christina Sylvest, Jonas Goldin Diness, Pim Gal
Přispěvatelé: Cardiology, ACS - Heart failure & arrhythmias
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Adult
Male
030213 general clinical medicine
medicine.medical_specialty
Adolescent
medicine.medical_treatment
Cmax
Cardioversion
Placebo
030226 pharmacology & pharmacy
Infusion Site
Severity of Illness Index
General Biochemistry
Genetics and Molecular Biology
Article
03 medical and health sciences
Electrocardiography
Potassium Channels
Calcium-Activated
Young Adult
0302 clinical medicine
Pharmacokinetics
Double-Blind Method
Heart Rate
Internal medicine
Atrial Fibrillation
medicine
Humans
General Pharmacology
Toxicology and Pharmaceutics
Infusions
Intravenous
Dose-Response Relationship
Drug
business.industry
General Neuroscience
Research
Atrial fibrillation
General Medicine
Articles
Middle Aged
medicine.disease
Healthy Volunteers
Injection Site Reaction
Tolerability
Pharmacodynamics
Cardiology
business
Anti-Arrhythmia Agents
Half-Life
Zdroj: Clinical and Translational Science
Gal, P, Klaassen, E S, Bergmann, K R, Saghari, M, Burggraaf, J, Kemme, M J B, Sylvest, C, Sørensen, U, Bentzen, B H, Grunnet, M, Diness, J G & Edvardsson, N 2020, ' First Clinical Study with AP30663-a K Ca 2 Channel Inhibitor in Development for Conversion of Atrial Fibrillation ', Clinical and Translational Science, vol. 13, no. 6, pp. 1336-1344 . https://doi.org/10.1111/cts.12835
Clinical and Translational Science, 13(6), 1336-1344. Wiley-Blackwell
ISSN: 1752-8062
1752-8054
Popis: Pharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca2+ activated K+ (KCa2) channel blocker, prolonged the atrial effective refractory period in preclinical studies and subsequently converted AF into normal sinus rhythm. This first-in-human study evaluated the safety and tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects were explored. Forty-seven healthy male volunteers (23.7 ± 3.0 years) received AP30663 intravenously in ascending doses. Due to infusion site reactions, changes to the formulation and administration were implemented in the latter 24 volunteers. Extractions from a 24-hour continuous electrocardiogram were used to evaluate the PD effect of AP30663. Data were analyzed with a repeated measure analysis of covariance, noncompartmental analysis, and concentration-effect analysis. In total, 33 of 34 adverse events considered related to AP30663 exposure were related to the infusion site, mild in severity, and temporary in nature, although full recovery took up to 110 days. After formulation and administration changes, the local infusion site reaction remained, but the median duration was shorter despite higher dose levels. AP30663 displayed a less than dose proportional increase in peak plasma concentration (Cmax) and a terminal half-life of around 5 hours. In healthy volunteers, no effect of AP30663 was observed on electrocardiographic parameters, other than a concentration-dependent effect on the corrected QT Fridericia’s formula interval (+18.8 ± 4.3 ms for the highest dose level compared with time matched placebo). In conclusion, administration of AP30663, a novel KCa2 channel inhibitor, was safe and well-tolerated systemically in humans, supporting further development in patients with AF undergoing cardioversion.
Databáze: OpenAIRE
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