Effects of oral administration of ibutamoren mesylate, a nonpeptide growth hormone 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 hypothalamic receptor that is different from the GH–releasing hormone receptor. We evaluated the safety and tolerability and the GH–insulin‐like growth factor (IGF) 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 velocity <10th percentile for age, height <10th percentile for age, and a maximum GH response of ≤10 μg/L to two different GH stimulation tests. The children were assigned as follows to one of three treatment 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, respectively) 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 before 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 baseline within each group. After administration of ibutamoren mesylate 0.8 mg/kg for 8 days (group III), the median increases (on day 15) from baseline were as follows: 3.8 μg/L (range, 0 to 34.3) for serum GH peak concentration ( P = .001), 4.3 μg · h/L (range, 1.3 to 35.6) for the GH area under the concentration‐time curve from time zero to 8 hours (AUC 0–8 ) ( P < .001), 12 μg/L (range, −4 to 116) for serum IGF‐I ( P = .01), and 0.4 μg/L (range, −0.9 to 1.5) for serum IGF‐binding protein 3 (IGFBP‐3) ( P = .01). There was no change in serum prolactin, glucose, triiodothyronine, thyroxine, thyrotropin, peak serum cortisol, and insulin concentrations or 24‐hour urinary free cortisol after administration of 0.8 mg/kg per day of ibutamoren mesylate for 8 days. We conclude that short‐term administration of ibutamoren mesylate can increase GH, IGF‐I, and IGFBP‐3 levels in some children with GH deficiency. Thus this compound is applicable for testing its effect on growth velocity. Clinical Pharmacology & Therapeutics (2001) 70 , 91–98; doi: 10.1067/mcp.2001.116514