title: QT interval correction assessment in the anesthetized guinea pig.
abstract: BACKGROUND
  The anesthetized guinea pig (ANES GP) has proven to be an effective small animal model to evaluate cardiac electrophysiologic effects of drug-candidate molecules during lead optimization. While heart rate (HR) corrected QT interval (QTc) is a key variable to determine test article-dependent repolarization effects, ideal correction methods are an area of constant debate given the potential influence of anesthesia, autonomic tone, species, strain and gender on the QT/HR relationship. The aim of this study was to characterize the ability of common correction formulas to normalize rate-dependent effects on the QT interval in the ketamine/xylazine ANES GP.
  
  
  METHODS
  Atrial pacing (n=10), ivabradine or ephedrine (n=6/group) infusions were used, respectively to evaluate the effects of a wide range of HRs on the QT/HR relationship. Correction formulas (Bazett [QTcb], Fridericia [QTcf] and Van de Water [QTcVdW]) were applied and the best fit formula was determined with the aid of the slope of their QT-HR linear relationship.
  
  
  RESULTS
  From 100 to 220bpm, QTcb underestimated the change in QT interval duration (QT/HR slope=0.35 to 0.67). However, QTcVdW was more appropriate in this HR range (QT/HR slope=-0.07 and 0.09). At higher HRs (>220bpm), QTcb performed better (QT/HR slope=-0.02 and 0.07) as compared to QTcf (QT/HR slope=-0.18 to -0.1) and QTcVdW (QT/HR slope=-0.2 to -0.17) (p<0.01). All the correction formulas identified dofetilide- and sotalol-dependent repolarization delay (n=6/group) but QTcb and QTcf demonstrated reduced sensitivity as compared to fixed cardiac pacing (p<0.01). In contrast, QTcVdW resulted in an apparent underestimation of the QT interval duration at HR levels above the basal ketamine/xylazine ANES GP HRs (>220bpm) with ephedrine (n=6).
  
  
  CONCLUSIONS
  The best fit correction formula in the ANES GP was highly dependent on the HR range. In the ketamine/xylazine model, QTcVdW performed best with HR <220bpm and QTcb performed best with HR >220bpm. The QTcVdW correction formula was thus selected in the ketamine/xylazine ANES GP since HRs in this model are generally within the optimal range for this correction formula.
authors.affiliation: Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA. Electronic address: pierre_morissette@merck.com.
authors.forename: Pierre
authors.initials: P
authors.lastname: Morissette
authors.affiliation: Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Hillary K
authors.initials: HK
authors.lastname: Regan
authors.affiliation: Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bernasconi
authors.affiliation: Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Gerenser
authors.affiliation: Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Travis
authors.affiliation: Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Fanelli
authors.affiliation: Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Frederick
authors.initials: F
authors.lastname: Sannajust
authors.affiliation: Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Regan
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D004562:Electrocardiography / Q000379:methods*; D004809:Ephedrine / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D000077550:Ivabradine; D007649:Ketamine / Q000008:administration & dosage; D008133:Long QT Syndrome / Q000175:diagnosis; D008297:Male; D023421:Models, Animal; D010627:Phenethylamines / Q000494:pharmacology*; D013015:Sotalol / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014991:Xylazine / Q000008:administration & dosage
chemical_list: D001552:Benzazepines; D010627:Phenethylamines; D013449:Sulfonamides; D014991:Xylazine; D000077550:Ivabradine; D007649:Ketamine; D013015:Sotalol; D004809:Ephedrine; C063533:dofetilide
keywords: Anesthetized guinea pig; Heart rate/QT correction; ICH S7A; ICH S7B; Paced guinea pig; Safety pharmacology