Use of hemodynamic profiling to explain toxicity observed following chronic dosing in rats

Abstract

This GLP study investigated a hemodynamic relationship to toxicity previously observed in a 28-day rat safety study following administration of Compound A. Naïve Sprague Dawley rats (5 M, 5 F) were instrumented with Data Sciences International HDS-11 implantable radiotelemetry devices to measure arterial blood pressure (BP), heart rate (HR) and body temperature (BT). Rats were dosed qd for 5 consecutive days with each treatment: vehicle (DI-water), 60 mg/kg/day (mpk) or 100 mpk of Compound A; up to 10 days of washout occurred between dose escalations. Hemodynamics were monitored (Ponemah v5.41) from 2 h prior to the first dose through 24 h after the final dose at each escalation. Data were analyzed as 1-h epochs; RANCOVA was done to determine statistical significance (p < 0.05). BP (mean; MAP, systolic; SAP; diastolic; DAP), pulse pressure (PP), HR and BT were relatively stable following all doses of vehicle. Administration of 60 and 100 mpk Compound A led to significant increases in MAP, SAP, DAP and PP in male rats, with a higher frequency of significant differences noted on earlier dosing days, suggesting tachyphylaxis associated with Compound A. In female rats, statistically significant MAP, SAP and DAP changes were bidirectional and intermittent following 60 mpk dosing and were predominantly increases after 100 mpk administration. Infrequent HR changes occurred in male rats following 60 mpk Compound A while more frequent significant HR decreases were seen on Days 3–5 following 100 mpk Compound A. Significant HR decreases occurred in females during the first 2 h after Compound A, with more frequent HR decreases noted on later dosing days following 100 mpk administration. Significant BT decreases occurred following dosing with both 60 and 100 mpk Compound A in male and female rats; magnitude and duration of significant decreases appeared dose-dependent. In conclusion, Compound A caused statistically significant changes in BP, HR and BT. The changes in hemodynamics observed during the first 5 days of dosing with Compound A are a possible contributing factor in the toxicity observed during prior 28-day rat safety assessments, demonstrating the sensitivity of this methodology to capture a dose-dependent response.