title: Cardiorespiratory safety evaluation in non-human primates.
abstract: BACKGROUND
  This study was designed to provide a comprehensive nonclinical respiratory safety pharmacology assessment using respiratory inductance plethysmography (RIP) concomitant with a standard cardiovascular (CV) safety assessment in non-human primates (NHP) in a single cardiorespiratory study.
  
  
  METHODS
  RIP calibration data were generated in conscious, ketamine-sedated, or propofol-anesthetized NHP to determine the most appropriate method. Calibration accuracy was assessed using a CO(2) rebreathe maneuver. Regardless of the technique, the RIP system reliably demonstrated accurate assessment of the CO(2) rebreathe response when expressed as a percent change with respect to control. Four male NHP were given single oral doses of vehicle, 1.25 and 5 mg/kg test article followed by 20 mg/kg repeatedly for 7 days. Telemetry-derived cardiovascular parameters (PR, QRS, QT, heart rate corrected QT (QTcR) intervals, blood pressure [BP], and heart rate [HR]) and RIP-derived respiratory parameters (respiration rate [RR], tidal volume [TV], and minute volume [MV]) were determined for 24 h pretest, 2 h predose and 24 h postdose.
  
  
  RESULTS
  A single dose of the test article at 5 or 20 mg/kg was associated with slight increases in HR, BP, RR, and MV at 2 to 7 h postdose, followed by decreases in HR, RR, TV, and MV at 5-23 h postdose. Decreases in HR, RR, TV, and MV were observed following 7 days of dosing at 20 mg/kg. Slight QTcR prolongation at 1 to 11 h postdose was observed following a single dose of 20 mg/kg.
  
  
  CONCLUSIONS
  These data show that the integrated assessment of cardiovascular and respiratory parameters in NHP is achievable continuously for at least 24 h postdose. The use of RIP as a method to assess the effects of a novel compound on the respiratory system complements, but does not interfere with, the cardiovascular assessment of new drugs.
authors.affiliation: Janssen Research and Development, LLC, Raritan, NJ, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ingram-Ross
authors.forename: Aidan K
authors.initials: AK
authors.lastname: Curran
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Miyamoto
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sheehan
authors.forename: Gareth
authors.initials: G
authors.lastname: Thomas
authors.forename: Johan
authors.initials: J
authors.lastname: Verbeeck
authors.forename: Eric J
authors.initials: EJ
authors.lastname: de Waal
authors.forename: Birgit
authors.initials: B
authors.lastname: Verstynen
authors.forename: Michael K
authors.initials: MK
authors.lastname: Pugsley
mesh_terms: D000818:Animals; D000830:Animals, Laboratory; D002138:Calibration; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D002319:Cardiovascular System / Q000187:drug effects*; D003243:Consciousness; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D064420:Drug-Related Side Effects and Adverse Reactions; D000882:Haplorhini / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D010991:Plethysmography; D012123:Pulmonary Ventilation / Q000187:drug effects / Q000502:physiology; D013686:Telemetry / Q000379:methods; D013990:Tidal Volume / Q000187:drug effects / Q000502:physiology