Exploratory safety investigations in normal, freely moving Göttingen Minipigs using telemetry: Pharmacological validation

Abstract

Introduction

Adverse cardiovascular (CV) effects is a major cause of drug attrition. Early assessment of CV risk for new drug candidates may be warranted for early de-risking of the further development. Predictive animal models and a careful study design are needed for decision-making. The aim of this study was to characterise the CV effects of three cardiometabolic compounds with known CV effects in humans – the GLP-1 receptor agonist liraglutide, the melanocortin receptor 4 agonist (MC4-RA) LY2112688 and urocortin-2 (UCN2) - in Göttingen Minipigs to evaluate the predictability of this model.

Materials and methods

Female Göttingen Minipigs with telemetry implants (n = 6–8) were used in 3 consecutive cross-over studies looking at CV effects of liraglutide, LY2112688 and UCN2. Main endpoints were: Mean arterial blood pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR), in addition to activity and body temperature.

Results

Liraglutide at the highest dose level of 3 nmol/kg (Day 7) induced a significant increase in 24 h HR (p < 0.01) compared to vehicle. No significant differences in MAP, SBP or DBP were observed. The MC4-RA LY2112688 at a dose level of 0.1–0.15 mg/kg (Day 4) gave rise to significant increases in all of 24 h HR (p < 0.05), MAP (p < 0.01), SBP (p < 0.01) and DBP (p < 0.05) compared to vehicle. UCN2 infusion resulted in a significant increase in HR (p < 0.05) and a significant decrease in SBP (p < 0.05).

Conclusion

The study highlights different CV study designs in Göttingen Minipigs and show that this model qualitatively reproduced the CV effects observed in humans following treatment with the three test compounds. These data support the minipig as a translational preclinical model for exploratory safety evaluations, although the magnitude of the changes may not translate completely between species.