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 < or = 10 microg/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 microg/L (range, 0 to 34.3) for serum GH peak concentration (P = .001), 4.3 microg x 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 microg/L (range, -4 to 116) for serum IGF-I (P = .01), and 0.4 microg/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.
Codner
E
E
Institute of Maternal and Child Research, University of Chile, Santiago, Chile. ecodner@machi.med.uchile.cl
Cassorla
F
F
Tiulpakov
A N
AN
Mericq
M V
MV
Avila
A
A
Pescovitz
O H
OH
Svensson
J
J
Cerchio
K
K
Krupa
D
D
Gertz
B J
BJ
Murphy
G
G
D000284:Administration, Oral; D002648:Child; D004311:Double-Blind Method; D005260:Female; D013006:Growth Hormone / Q000172:deficiency* / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008661:Metabolism, Inborn Errors / Q000188:drug therapy* / Q000378:metabolism; D013141:Spiro Compounds / Q000008:administration & dosage* / Q000494:pharmacology*; D016896:Treatment Outcome
D007211:Indoles; D018972:Insulin-Like Growth Factor Binding Protein 3; D013141:Spiro Compounds; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C094817:ibutamoren mesylate