Cardiovascular and respiratory safety pharmacology in Gottingen minipigs: Pharmacological characterization

Introduction: Similarities between pigs and humans support the relevance of Gottingen minipigs for regulatory safety pharmacology. The minipig is the species of choice for cardiovascular safety pharmacology when pivotal repeat toxicology studies are conducted in this species. Methods: 4 male Gottingen minipigs with cardiovascular telemetry transmitters received intravenous saline, esmolol (0.5, 1, 2, 4 and 8 mg/kg), medetomidine (0.04 mg/kg), remifentanil (0.5, 1, 2, 4, 8 and 16 mu g/kg) and dopamine (2, 8, 10, 20, 30 and 50 mu g/kg/min) and oral sotalol, (3 and 10 mg/kg). Respiratory monitoring was conducted in 3 male and 3 female Gottingen minipigs receiving intravenous saline and methacholine (0, 3.4, 13.5 and 68 mu g/kg). Results: Heart rate (HR) corrected QT was optimal with a method based on analysis of covariance (QTca) followed by Fridericia's standard formula. Esmolol induced a decrease in HR. Medetomidine was associated with an initial hypertension with bradycardia followed by sustained hypotension, bradycadia and prolonged QTc. Remifentanil induced a dose-dependent QTc shortening with an increase in arterial pressures. Sotalol caused a decrease in HR and systolic arterial pressure with an increase in PR and QTc intervals. Dopamine induced an increase in arterial and pulse pressures. Methacholine increased tidal volume, respiratory rate and minute volume. Discussion: The results suggest that the minipig is a valid alternative to other non-rodent species for cardiovascular and respiratory safety pharmacology studies when this species is justified. (C) 2011 Elsevier Inc. All rights reserved.