Rabbits are a suitable animal model for the pre-clinical development of growth hormone agonists and antagonists

• Published in: Experimental and Clinical Endocrinology & Diabetes
• Main Authors: Bielohuby, M, Zarkesh-Esfahani, SH, Manolopoulou, J, Khorasgani, MT, Aghili, ZS, Wilkinson, IR, Ross, RJ, Bidlingmaier, M
• Format: Conference Proceeding
• Language: English
• Published: 05.03.2014
• ISSN: 0947-7349; 1439-3646
• DOI: 10.1055/s-0034-1372159

Development of new growth hormone (GH) agonists and antagonists requires animal models for pre-clinical testing. Ideally, in such models effects of treatment can be monitored using the same pharmacodynamic (PD) markers later used in clinical practice. For GH, IGF-I is the most important PD marker. However, in intact rodents IGF-I shows no response to recombinant human GH (rhGH) administration, and there is little evidence for effects of GH antagonists except when administered at very high dose or expressed in transgenic mice. We therefore explored whether intact rabbits could be a better laboratory animal model to test GH agonists and antagonists by monitoring IGF-I. Methods: As none of the commercially available IGF-I assays is validated for rabbit IGF-I, we tested precision, sensitivity, linearity, and recovery using the automated iSYS IGF-I assay (IDS, Boldon, UK) in rabbit serum. IGF-I was also measured in rabbits of different strains, age groups and sexes, and in rabbits (n = 6 – 10/group) treated with rhGH (Norditropin, Novo Nordisk; 1 mg/kg), GH antagonist (Somavert, Pfizer, 1 mg/kg) or PBS (control). Results: Precision (1.7 – 3.3% CV) and linearity (90.4 – 105.6%) of the assay were good in rabbit samples. Compared to recombinant human IGF-I, recovery was threefold lower for recombinant rabbit IGF-I. IGF-I was affected by sex, age and genetic background. In contrast to rodents, rabbits displayed a significant rise in IGF-I 24h after a single rhGH injection (286 ± 22 vs. 434 ± 26 ng/ml; p < 0.01). GHA treatment lowered IGF-I from the fourth injection onwards (323 ± 17 vs. 212 ± 29 ng/ml; p < 0.01). We conclude that the IDS-iSYS IGF-I assay can also be used to measure IGF-I in rabbits. Similar to rodents, rabbits display variations in IGF-I depending on sex, age and genetic background. Unlike in rodents, the IGF-I response to rhGH or GHA treatment in rabbits mimics the pharmacodynamics seen in humans, thus suggesting rabbits as a suitable model to test GH agonists and antagonists.