title: Shortening of the electromechanical window in the ketamine/xylazine-anesthetized guinea pig model to assess pro-arrhythmic risk in early drug development.
abstract: BACKGROUND
  A negative electromechanical window (EMw) was recently proposed as a better preclinical tool than QTc interval to predict clinical pro-arrhythmic potential. As such, we utilized the ketamine/xylazine anesthetized guinea pig to characterize the EMw and QTc interval for a diverse set of reference agents with known clinical pro-arrhythmic potential. Then we determined the clinical proarrhythmia predictive capacity of EMw shortening compared to hERG inhibition or QTc interval prolongation alone.
  
  
  METHODS
  Changes in EMw and QTc interval by 26 reference agents were evaluated in the ketamine/xylazine-anesthetized guinea pig. Confusion matrix analysis using the hERG, QTc and EMw indexes (hERG IC50, QTc EC5 or the EMw EC-10 divided by their respective free therapeutic maximal plasma concentration) at various folds the therapeutic concentrations was conducted to assess the concordance of each index to predict clinical pro-arrhythmic risk.
  
  
  RESULTS
  Shortening of the EMw concomitant to an increase in QTc interval was observed in the GP with known pro-arrhythmic drugs. Non-torsadogenic compounds did not cause EMw shortening, although some prolonged the QTc interval. The preclinical:clinical concordance of the EMw index (88%) was similar (p>0.05) to using QTc interval prolongation alone (85%) but significantly greater (p<0.05) than using hERG inhibition alone (69%). In addition, the specificity when using the EMw (87%) was largely greater (p<0.05) than using QTc interval (73%) or hERG inhibition (60%) alone. When the components of the response (duration of left ventricular pressure (LVP) cycle (QLVPend) or QT interval) that caused EMw shortening were considered, the concordance is further improved (>95%).
  
  
  CONCLUSIONS
  EMw shortening improves QTc interval prolongation recording in early drug development and increases the translatability over existing preclinical tools in predicting clinical arrhythmias.
authors.affiliation: SALAR-Safety & Exploratory Pharmacology Department, Merck Research Laboratories, West Point, PA, USA. Electronic address: pierre_morissette@merck.com.
authors.forename: P
authors.initials: P
authors.lastname: Morissette
authors.affiliation: SALAR-Safety & Exploratory Pharmacology Department, Merck Research Laboratories, West Point, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Regan
authors.affiliation: SALAR-Safety & Exploratory Pharmacology Department, Merck Research Laboratories, West Point, PA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: SALAR-Safety & Exploratory Pharmacology Department, Merck Research Laboratories, West Point, PA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Gerenser
authors.affiliation: SALAR-Safety & Exploratory Pharmacology Department, Merck Research Laboratories, West Point, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Travis
authors.affiliation: SALAR-Safety & Exploratory Pharmacology Department, Merck Research Laboratories, West Point, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: SALAR-Safety & Exploratory Pharmacology Department, Merck Research Laboratories, West Point, PA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Fanelli
authors.affiliation: SALAR-Safety & Exploratory Pharmacology Department, Merck Research Laboratories, West Point, PA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Sannajust
mesh_terms: D000316:Adrenergic alpha-Agonists; D000758:Anesthesia; D000778:Anesthetics, Dissociative; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology*; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007649:Ketamine; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects; D014991:Xylazine
chemical_list: D000316:Adrenergic alpha-Agonists; D000778:Anesthetics, Dissociative; D014991:Xylazine; D007649:Ketamine
keywords: Anesthetized guinea pig; Electromechanical window; QT corrected interval; Safety pharmacology; Torsades de Pointes; hERG inhibition