The pharmacokinetics, pharmacodynamics, safety and tolerability following 7 days daily oral treatment with NN703 in healthy male subjects.
The aim of the present study was to assess the safety, pharmacokinetics and pharmacodynamics (including specificity) of NN703 (tabimorelin), a growth hormone (GH) secretagogue, in healthy male subjects following treatment for 7 days once-daily. This was a randomized, double-blind and placebo-controlled study with four active dose levels: 1.71, 3.0, 4.5 and 6.86 mg/kg body weight. There was a dose-related increase for GH area under the curve (AUC) (0-12 h) and GH C(max)(0--12 h); these were significantly higher on both days 1 and 7 as compared with placebo treatment (P = 0.04 to P< 0.0001); however, an overall significant decrease in GH release was found from day 1 to day 7 (P< 0.001). Insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) increased at all dose levels (including placebo); however, a significantly higher increase as compared with placebo treatment was observed at the three highest dose levels for IGF-I (P = 0.04--0.0006) and at the highest dose level for IGFBP-3 (P = 0.03). There was no statistically significant increase in AUC (0-5 h) for follicle-stimulating hormone, luteinizing hormone and cortisol between active and placebo treatment for day 1 or 7. On day 1 only, a statistically significant increase in AUC (0--5 h) was found for prolactin at 1.71 and 6.86 mg/kg (P< 0.05), for thyroid-stimulating hormone (TSH) at 3.0 mg/kg (P< 0.01) and for adrenocorticotrophic hormone (ACTH) at 4.5 mg/kg (P< 0.05); however, no dose--response relationship was observed for TSH or ACTH. In addition, a statistically significant decrease in AUC (0--5 h) for ACTH (3.0 and 6.86 mg/kg) and cortisol (1.71 mg/kg) was observed on day 7 (P< 0.05). Thus, NN703 is a promising candidate for treatment of absolute or relative GH deficiency.
Zdravkovic
M
M
Department of Clinical Pharmacology, Novo Nordisk A/S, 2880 Bagsvaerd, Denmark. mzd@novonordisk.com
Christiansen
T
T
Eliot
L
L
Agersoe
H
H
Thomsen
M S
MS
Falch
J F
JF
Søgaard
B
B
Ynddal
L
L
Ilondo
M M
MM
D000284:Administration, Oral; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D019540:Area Under Curve; D001835:Body Weight; D004151:Dipeptides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D010919:Placebos; D013972:Thyrotropin / Q000378:metabolism; D013997:Time Factors
D004151:Dipeptides; D010919:Placebos; D000324:Adrenocorticotropic Hormone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D013972:Thyrotropin; C120631:tabimorelin; D006854:Hydrocortisone