MK-0448, a specific Kv1.5 inhibitor: safety, pharmacokinetics, and pharmacodynamic electrophysiology in experimental animal models and humans.
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.


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 atrial fibrillation was terminated with bolus intravenous MK-0448 doses of 0.03 and 0.1 mg/kg. These data led to a 2-part first-in-human study: Part I evaluated safety and pharmacokinetics, and part II was an invasive electrophysiological study in healthy subjects. MK-0448 was well-tolerated with mild adverse experiences, most commonly irritation at the injection site. During the electrophysiological 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 μmol/L. 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.
Department of Medicine, Division of Cardiology, Thomas Jefferson University, Philadelphia, PA, USA.
Behzad B
BB
Pavri
Howard E
HE
Greenberg
Walter K
WK
Kraft
Nicole
N
Lazarus
Joseph J
JJ
Lynch
Joseph J
JJ
Salata
Mark T
MT
Bilodeau
Christopher P
CP
Regan
Gary
G
Stump
Li
L
Fan
Anish
A
Mehta
John A
JA
Wagner
David E
DE
Gutstein
Daniel
D
Bloomfield
D000328:Adult; D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology / Q000517:prevention & control*; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006329:Heart Conduction System / Q000502:physiology; D006333:Heart Failure / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D066298:In Vitro Techniques; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D008297:Male; D026902:Potassium Channel Blockers / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D012849:Sinoatrial Node / Q000502:physiology; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D014630:Vagus Nerve / Q000502:physiology
D051668:Delayed Rectifier Potassium Channels; D051666:Kv1.5 Potassium Channel; C578461:N-(6-(1-(4-fluorophenyl)-2,2-di(pyridin-3-yl)ethyl)pyridin-2-yl)methanesulfonamide; D026902:Potassium Channel Blockers; D011725:Pyridines; D013449:Sulfonamides