title: Statistical power analysis of cardiovascular safety pharmacology studies in conscious rats.
abstract: Cardiovascular (CV) toxicity and related attrition are a major challenge for novel therapeutic entities and identifying CV liability early is critical for effective derisking. CV safety pharmacology studies in rats are a valuable tool for early investigation of CV risk. Thorough understanding of data analysis techniques and statistical power of these studies is currently lacking and is imperative for enabling sound decision-making.
  
  
  METHODS
  Data from 24 crossover and 12 parallel design CV telemetry rat studies were used for statistical power calculations. Average values of telemetry parameters (heart rate, blood pressure, body temperature, and activity) were logged every 60s (from 1h predose to 24h post-dose) and reduced to 15min mean values. These data were subsequently binned into super intervals for statistical analysis. A repeated measure analysis of variance was used for statistical analysis of crossover studies and a repeated measure analysis of covariance was used for parallel studies. Statistical power analysis was performed to generate power curves and establish relationships between detectable CV (blood pressure and heart rate) changes and statistical power. Additionally, data from a crossover CV study with phentolamine at 4, 20 and 100mg/kg are reported as a representative example of data analysis methods.
  
  
  RESULTS
  Phentolamine produced a CV profile characteristic of alpha adrenergic receptor antagonism, evidenced by a dose-dependent decrease in blood pressure and reflex tachycardia. Detectable blood pressure changes at 80% statistical power for crossover studies (n=8) were 4-5mmHg. For parallel studies (n=8), detectable changes at 80% power were 6-7mmHg. Detectable heart rate changes for both study designs were 20-22bpm.
  
  
  CONCLUSIONS
  Based on our results, the conscious rat CV model is a sensitive tool to detect and mitigate CV risk in early safety studies. Furthermore, these results will enable informed selection of appropriate models and study design for early stage CV studies.
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT, USA. Electronic address: Siddhartha.Bhatt@pfizer.com.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Bhatt
authors.affiliation: Regulatory Strategy and Compliance, Pfizer Worldwide Research and Development, Groton, CT, USA.
authors.forename: Dingzhou
authors.initials: D
authors.lastname: Li
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT, USA.
authors.forename: Declan
authors.initials: D
authors.lastname: Flynn
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Wisialowski
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, La Jolla, CA, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Hemkens
authors.affiliation: Global Safety Pharmacology, Pfizer Worldwide Research and Development, Groton, CT, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Steidl-Nichols
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000633:toxicity; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000503:physiopathology*; D003243:Consciousness; D018592:Cross-Over Studies; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010600:Pharmacology / Q000706:statistics & numerical data*; D010646:Phentolamine / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012107:Research Design; D012449:Safety / Q000706:statistics & numerical data*; D013686:Telemetry
chemical_list: D000317:Adrenergic alpha-Antagonists; D010646:Phentolamine
keywords: Cardiovascular; Data analysis; Methods; Phentolamine; Rat; Statistical power; Telemetry