title: Evaluation of cardiovascular changes in dogs administered three positive controls using jacketed external telemetry-blood pressure (JET-BP).
abstract: BACKGROUND
  Nonclinical safety studies are increasingly incorporating cardiac safety endpoints to discover potential cardiovascular liabilities. This trend for more thorough cardiovascular nonclinical safety evaluation is prudent given the high attrition rate of potential therapeutics due to unexpected cardiovascular liabilities discovered in late-stage clinical trials or post-market approval. In particular, the causal relationship of blood pressure changes that lead to risk of major adverse cardiac events suggests hemodynamic changes should be critically evaluated in preclinical studies of novel therapeutics.
  
  
  METHODS
  Jacketed external telemetry with an implanted miniature blood pressure transmitter (JET-BP) was used to characterize the tolerability, functionality, and sensitivity of this study design in dogs. Thirty-six male or female beagles (n=6 dogs/sex/group) were administered vehicle control (reverse osmosis water) or etilefrine (1, 10mg/kg), sotalol (3, 30mg/kg), and hydralazine (1, 10mg/kg) on separate days. Telemetry data were evaluated for positive control article-related changes and retrospective power analysis was also completed. Animals were evaluated for instrumentation-related changes in clinical and anatomic pathology endpoints.
  
  
  RESULTS
  All three positive controls elicited the expected pharmacologic responses that were statistically different at high and low doses. Retrospective power analysis confirmed this study design was able to statistically differentiate minor (approximately 5 to 15%) changes in electrocardiography and blood pressure values. This study also demonstrated the potential advantages of combining cardiovascular data across sex when the test article exposure and pharmacodynamics were consistent. Data collection using miniature telemetry blood pressure transmitters did not result in anatomic or clinical pathology findings that would prevent their use in general toxicology studies.
  
  
  CONCLUSIONS
  This characterization study indicates that JET-BP in dogs offers a scientifically-robust method to evaluate novel therapeutics for potential cardiovascular liabilities.
authors.affiliation: Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, WI 53704-2523, USA. Electronic address: john.kremer@covance.com.
authors.forename: John J
authors.initials: JJ
authors.lastname: Kremer
authors.affiliation: Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, WI 53704-2523, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bills
authors.affiliation: Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, WI 53704-2523, USA.
authors.forename: Nathanael J
authors.initials: NJ
authors.lastname: Hanke
authors.affiliation: Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, WI 53704-2523, USA.
authors.forename: Hepei
authors.initials: H
authors.lastname: Chen
authors.affiliation: Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, WI 53704-2523, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Meier
authors.affiliation: Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, WI 53704-2523, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Osinski
authors.affiliation: Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, WI 53704-2523, USA.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Foley
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D066126:Cardiotoxicity / Q000175:diagnosis*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004562:Electrocardiography / Q000379:methods; D005039:Etilefrine / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006830:Hydralazine / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D012107:Research Design; D013015:Sotalol / Q000008:administration & dosage / Q000494:pharmacology; D013686:Telemetry / Q000379:methods*
chemical_list: D006830:Hydralazine; D013015:Sotalol; D005039:Etilefrine
keywords: Blood pressure; Cardiovascular; Dogs; Electrocardiography; Methods; Nonclinical; Power analysis; QT interval; Safety pharmacology; Telemetry