MK-0448, a Specific Kv1.5 Inhibitor: Safety, Pharmacokinetics and Pharmacodynamic Electrophysiology in Experimental Animal Models and in Humans.

Authors

Behzad B. Pavri, Thomas Jefferson UniversityFollow
Howard E Greenberg, Thomas Jefferson UniversityFollow
Walter K. Kraft, Thomas Jefferson UniversityFollow
Nicole Lazarus, Merck Sharp & Dohme Corp.
Joseph J Lynch, Merck Sharp & Dohme Corp.
Joseph J Salata, Merck Sharp & Dohme Corp.
Mark T Bilodeau, Merck Sharp & Dohme Corp.
Christopher P Regan, Merck Sharp & Dohme Corp.
Gary Stump, Merck Sharp & Dohme Corp.
Li Fan, Merck Sharp & Dohme Corp.
Anish Mehta, Merck Sharp & Dohme Corp.Follow
John A Wagner, Merck Sharp & Dohme Corp.Follow
David E Gutstein, Merck Sharp & Dohme Corp.Follow
Daniel Bloomfield, Merck Sharp & Dohme Corp.

Document Type

Article

Publication Date

10-11-2012

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Circulation. Arrhythmia and electrophysiology. October 11, 2012

The published version is available at PMID: 23060423. Copyright © American Heart Association Inc.

Abstract

BACKGROUND: -We evaluated the viability of I(Kur) as a target for maintenance of sinus rhythm in patients with a history of atrial fibrillation through the testing of MK-0448, a novel I(Kur) inhibitor. METHODS AND RESULTS: -In vitro MK-0448 studies demonstrated strong inhibition of I(Kur) with minimal off-target activity. In vivo MK-0448 studies in normal anesthetized dogs demonstrated significant prolongation of the atrial refractory period compared with vehicle controls without affecting the ventricular refractory period. In studies of a conscious dog heart failure model, sustained AF was terminated with bolus intravenous MK-0448 doses of 0.03 and 0.1 mg/kg. These data led to a two-part "first-in-human" study: Part I evaluated safety and pharmacokinetics, and Part II was an invasive electrophysiologic (EP) study in healthy subjects. MK-0448 was well-tolerated with mild adverse experiences, most commonly irritation at the injection site. During the EP study, ascending doses of MK-0448 were administered, but no increases in atrial or ventricular refractoriness were detected despite achieving plasma concentrations in excess of 2 μM. Follow-up studies in normal anesthetized dogs designed to assess the influence of autonomic tone demonstrated that prolongation of atrial refractoriness with MK-0448 was markedly attenuated in the presence of vagal nerve simulation, suggesting that the effects of I(Kur) blockade on atrial repolarization may be negated by enhanced parasympathetic neural tone. CONCLUSIONS: -The contribution of I(Kur) to human atrial electrophysiology is less prominent than in preclinical models and therefore is likely to be of limited therapeutic value for the prevention of atrial fibrillation.

Recommended Citation

Pavri, Behzad B.; Greenberg, Howard E; Kraft, Walter K.; Lazarus, Nicole; Lynch, Joseph J; Salata, Joseph J; Bilodeau, Mark T; Regan, Christopher P; Stump, Gary; Fan, Li; Mehta, Anish; Wagner, John A; Gutstein, David E; and Bloomfield, Daniel, "MK-0448, a Specific Kv1.5 Inhibitor: Safety, Pharmacokinetics and Pharmacodynamic Electrophysiology in Experimental Animal Models and in Humans." (2012). Department of Pharmacology and Experimental Therapeutics Faculty Papers. Paper 40.
https://jdc.jefferson.edu/petfp/40

PubMed ID

23060423