Cardiorespiratory safety evaluation in non-human primates.

INTRODUCTION: 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.
CONCLUSION: 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.