Effects of oral administration of ibutamoren mesylate, a nonpeptide growthhormone secretagogue, on the growth hormone-insulin-like growth factor I axis in growth hormone-deficient children

Ibutamoren mesylate (MK-0677), an orally active nonpeptide growth hormone ( GH) secretagogue, stimulates GH release through a pituitary and hypothalami c receptor that is different from the GH-releasing hormone receptor. We eva luated the safety and tolerability and the GH-insulin-like growth factor (I GF) responses to two dosages of oral ibutamoren mesylate given to children with GH deficiency for 7 to 8 days. The patients, 18 prepubertal children ( 15 male, 3 female) with idiopathic GH deficiency, had a chronologic age of 10.6 +/- 0.8 years (mean +/- SD), bone age of 7.4 +/- 0.7 years, growth vel ocity <10th percentile for age, height <10th percentile for age, and a maxi mum GH response of less than or equal to 10 mug/L to two different GH stimu lation tests. The children were assigned as follows to one of three treatme nt groups with ibutamoren mesylate: 0.2 mg/kg per day for 7 days (days 1-7 or 8-14) and matching placebo for the alternate 7 days (groups I and II, re spectively) or 0.8 mg/kg per day for 7 days (days 8-14, group III). On day 15 all patients received an 0.8-mg/kg dose of ibutamoren mesylate. Patients in groups I and II were studied first to assess safety at the low dose bef ore advancement to the high dose. Hormonal profiles were evaluated on day-1 (baseline) and day 15, and the results were expressed as the change from b aseline within each group. After administration of ibutamoren mesylate 0.8 mg/kg for 8 days (group III), the median increases (on day 15) from baselin e were as follows: 3.8 mug/L (range, 0 to 34.3) for serum GH peak concentra tion (P = .001), 4.3 mug . h/L (range, 1.3 to 35.6) for the GH area under t he concentration-time curve from time zero to 8 hours (AUC(0-8)) (P < .001) , 12 <mu>g/L (range, -4 to 116) for serum IGF-I (P = .01), and 0.4 mug/L (r ange, -0.9 to 1.5) for serum IGF-binding protein 3 (IGFBP-3) (P = .01). The re was no change in serum prolactin, glucose, triiodothyronine, thyroxine, thyrotropin, peak serum cortisol, and insulin concentrations or 24-hour uri nary free cortisol after administration of 0.8 mg/kg per day of ibutamoren mesylate for 8 days. We conclude that short-term administration of ibutamor en mesylate can increase GH, IGF-I, and IGFBP-3 levels in some children wit h GH deficiency. Thus this compound is applicable for testing its effect on growth velocity.