Pharmacokinetic and pharmacodynamic modeling of NN703, a growth hormone secretagogue, after a single po dose to human volunteers

• Published in: Journal of clinical pharmacology Vol. 41; no. 2; p. 163
• Main Authors: Agersø, H, Ynddal, L, Søgaard, B, Zdravkovic, M
• Format: Journal Article
• Language: English
• Published: England 01.02.2001
• Subjects: Administration, Oral; Adult; Dipeptides - blood; Dipeptides - pharmacokinetics; Dipeptides - pharmacology; Dose-Response Relationship, Drug; Double-Blind Method; Growth Hormone - metabolism; Humans; Male; Models, Biological
• ISSN: 0091-2700
• DOI: 10.1177/00912700122009971

The objective of this study was to describe the pharmacokinetics and pharmacodynamics of NN703, a growth hormone (GH)-releasing secretagogue, after po administration to healthy human male subjects. The study was designed as a randomized, placebo-controlled, double-blind, dose-escalating, single-dose trial of NN703 covering eight dose levels. Each of the dose levels had 6 subjects on active treatment and 2 subjects on placebo. NN703 was administered po as a solution. Blood samples for serum concentrations of NN703 and GH were collected before dosing and up to 24 hours after dosing. Serum concentrations of NN703 were determined using a validated analytical method, based on solid-phase extraction and LC/MS/MS detection. A two-compartmental model with zero-order input was used to describe the pharmacokinetics of NN703. The parameters of the elimination phase were fitted simultaneously, whereas the parameters describing the absorption phase were allowed to vary between the dose levels. The pharmacodynamics of NN703 was described by use of an indirect-response model containing both a threshold value and a modulator for the development of tolerance. It was concluded that the absorption of NN703 after po administration was nonlinear; the bioavailability increased with the dose. The serum concentration of NN703 required for half-maximal stimulation of GH was determined to be 485 ng/ml. The proposed indirect-response model requiring a threshold concentration and development of tolerance provided a useful mean of quantifying the effects of NN703. Furthermore, the development of tolerance shown based on pharmacokinetic/pharmacodynamic modeling of single-dose data presented here has been confirmed following multiple dosing in healthy male subjects.