2015 ACVIM Forum Research Abstract Program

Capromorelin at daily doses up to 52.4 mg/kg (approximately 17.5X the active ingredient concentration in the proposed clinical dose for dogs) for 12 months resulted in minimal toxicity with no negative effects on food consumption, body weight, ophthalmic exams, vital signs or gross pathology. Clinical signs related to capromorelin were limited to salivation and loose stool noted sporadically during the study. Occasional episodes of emesis were observed and considered unrelated to treatment. The higher dose treatments were associated with an increased incidence of reddening/swollen paws. One dog in the 52.4 mg/kg group died when capromorelin was accidentally delivered into the respiratory tract during gavage as confirmed by necropsy. Electrocardiogram data indicated slight increases in the PRQ interval in the 52.4 mg/kg and 9.2 mg/kg groups 1-2 hours following dosing. However, no histological lesions were observed in the heart. In general, clinical pathology and urinalysis parameters were within normal ranges or lacked a consistent dose/time relationship. However, there were slight decreases in red blood cells, hemoglobin and hematocrit that did not appear to be clinically significant in the 52.4 mg/ kg group. Cholesterol, HDL and alkaline phosphatase serum levels were statistically significantly increased in the 52.4 mg/kg group compared to placebo and individual animal values tended to be at the high end or slightly above the normal reference range. Increased absolute liver weights in dogs treated with the 52.4 mg/kg dose of capromorelin were noted. A slight increase in hepatocellular cytoplasmic vacuolation was seen in all capromorelin treated groups. Capromorelin plasma levels increased with increasing dose, were similar on Days 90, 181 and 349 indicating no accumulation of drug and there were no gender-related differences. GH plasma levels increased modestly as expected on Days 1, 170 and 351 following capromorelin treatment. The GH response was controlled by a physiological negative feedback so that the magnitude of the GH response to capromorelin treatment lessened over time. As expected, IGF-1 plasma levels increased following capromorelin treatment and increased levels were sustained over time as evidenced in plasma collected on 1, 7, 14, 21, 28, 62, 121, 170 and 351. The results of this study demonstrated that capromorelin was well-tolerated in dogs dosed up to 52.4 mg/kg for 12 months. Further, this study indicates an expected wide safety margin for capromorelin as the high dose is approximately 17.5X the proposed clinical dose.