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The KCa2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs.

ABSTRACT: Aims:To describe the effects of the KCa2 channel inhibitor AP30663 in pigs regarding tolerability, cardiac electrophysiology, pharmacokinetics, atrial functional selectivity, effectiveness in cardioversion of tachy-pacing induced vernakalant-resistant atrial fibrillation (AF), and prevention of reinduction of AF. Methods and Results:Six healthy pigs with implanted pacemakers and equipped with a Holter monitor were used to compare the effects of increasing doses (0, 5, 10, 15, 20, and 25 mg/kg) of AP30663 on the right atrial effective refractory period (AERP) and on various ECG parameters, including the QT interval. Ten pigs with implanted neurostimulators were long-term atrially tachypaced (A-TP) until sustained vernakalant-resistant AF was present. 20 mg/kg AP30663 was tested to discover if it could successfully convert vernakalant-resistant AF to sinus rhythm (SR) and protect against reinduction of AF. Seven anesthetized pigs were used for pharmacokinetic experiments. Two pigs received an infusion of 20 mg/kg AP30663 over 60 min while five pigs received 5 mg/kg AP30663 over 30 min. Blood samples were collected before, during, and after infusion on AP30663. AP30663 was well-tolerated and prominently increased the AERP in pigs with little effect on ventricular repolarization. Furthermore, it converted A-TP induced AF that had become unresponsive to vernakalant, and it prevented reinduction of AF in pigs. Both a >30 ms increase of the AERP and conversion of AF occurred in different pigs at a free plasma concentration level of around 1.0-1.4 µM of AP30663, which was achieved at a dose level of 5 mg/kg. Conclusion:AP30663 has shown properties in animals that would be of clinical interest in man.

SUBMITTER: Diness JG

PROVIDER: S-EPMC7059611 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The K<sub>Ca</sub>2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs.

Diness Jonas Goldin JG Kirchhoff Jeppe Egedal JE Speerschneider Tobias T Abildgaard Lea L Edvardsson Nils N Sørensen Ulrik S US Grunnet Morten M Bentzen Bo Hjorth BH

Frontiers in pharmacology 20200228

<h4>Aims</h4>To describe the effects of the K<sub>Ca</sub>2 channel inhibitor AP30663 in pigs regarding tolerability, cardiac electrophysiology, pharmacokinetics, atrial functional selectivity, effectiveness in cardioversion of tachy-pacing induced vernakalant-resistant atrial fibrillation (AF), and prevention of reinduction of AF.<h4>Methods and results</h4>Six healthy pigs with implanted pacemakers and equipped with a Holter monitor were used to compare the effects of increasing doses (0, 5, 1 ...[more]

PMID: 32180722

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Project description:Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with significant health risks. One strategy to mitigate the risks associated with long-term AF is to convert AF to sinus rhythm (SR). This study assessed the efficacy and safety of vernakalant hydrochloride for the pharmacological conversion of AF to SR.Patients with recent-onset (duration >3 h-???7 days) symptomatic AF and no evidence or history of congestive heart failure were randomized in a 2:1 ratio to receive vernakalant or placebo. Patients received an infusion of vernakalant (3 mg/kg) or placebo over 10 min, followed by a second infusion of vernakalant (2 mg/kg) or placebo 15 min later if AF had not been terminated. The primary efficacy endpoint was conversion of AF to SR for at least 1 min within 90 min of the start of drug infusion. The primary safety endpoint was a composite of: occurrence of clinically significant hypotension, clinically significant ventricular arrhythmia (including torsades de pointes, ventricular tachycardia or ventricular fibrillation) or death within 2 h of starting the drug infusion.A total of 217 patients were randomized to receive vernakalant (n?=?145) or placebo (n?=?72). Of the 129 individuals who received vernakalant, 59 (45.7 %) converted to SR compared with one of the 68 patients (1.5 %) who received placebo (p?<?0.0001). Conversion to SR was significantly faster with vernakalant than with placebo (p?<?0.0001), and a greater proportion of patients who received vernakalant than those who received placebo reported no AF-related symptoms at 90 min (p?=?0.0264). The primary composite safety endpoint was observed in one patient receiving vernakalant and in no patients receiving placebo. In the vernakalant arm, dysgeusia, paraesthesia and sneezing were the most common treatment-emergent adverse events, and three serious adverse events occurred that were considered to be related to study drug.Vernakalant resulted in rapid cardioversion of recent-onset AF in almost half of the study population and was generally well tolerated. The safety outcomes affirmed the need for careful selection and management of haemodynamically stable candidates for cardioversion.NCT00989001 .

Dataset Information

The KCa2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs.

Publications

The K<sub>Ca</sub>2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs.

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