• Exploratory safety investigati...

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

Title:
Exploratory safety investigations in normal, freely moving Göttingen Minipigs using telemetry: Pharmacological validation.
Authors:
Jacobsen J; Integrated Physiology Research, Novo Nordisk A/S, Måløv, Denmark., Christoffersen BØ; Integrated Physiology Research, Novo Nordisk A/S, Måløv, Denmark. Electronic address: BQC@novonordisk.com.
Source:
Journal of pharmacological and toxicological methods [J Pharmacol Toxicol Methods] 2025 Dec; Vol. 136, pp. 108395. Date of Electronic Publication: 2025 Sep 09.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Elsevier Country of Publication: United States NLM ID: 9206091 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-488X (Electronic) Linking ISSN: 10568719 NLM ISO Abbreviation: J Pharmacol Toxicol Methods Subsets: MEDLINE
Imprint Name(s):
Original Publication: New York, NY : Elsevier, c1992-
MeSH Terms:
Telemetry*/methods , Liraglutide*/pharmacology , Liraglutide*/adverse effects, Animals ; Swine, Miniature ; Swine ; Female ; Heart Rate/drug effects ; Blood Pressure/drug effects ; Cross-Over Studies ; Body Temperature/drug effects ; Dose-Response Relationship, Drug
Contributed Indexing:
Keywords: Activity; Blood pressure; Body temperature; Heart rate; Liraglutide; MC-4; Urocortin 2
Substance Nomenclature:
839I73S42A (Liraglutide)
Entry Date(s):
Date Created: 20250911 Date Completed: 20251217 Latest Revision: 20251217
Update Code:
20251218
DOI:
10.1016/j.vascn.2025.108395
PMID:
40934983
Database:
MEDLINE

Weitere Informationen

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.
(Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Declaration of competing interest BØC and JJ are employees at Novo Nordisk A/S and BØC is minor share holder.