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

The objective of this study was to describe the pharmacokinetics and pharma codynamics 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 s ubjects on active treatment and 2 subjects on placebo. NN703 was administer ed 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 concen trations of NN703 were determined using a validated analytical method, base d on solid-phase extraction and LC/MS/MS detection. A two-compartmental mod el with zero-order input was used to describe the pharmacokinetics of NN703 . The parameters of the elimination phase were fitted simultaneously wherea s the parameters describing the absorption phase were allowed to vary betwe en the dose levels. The pharmacodynamics of NN703 was described by use of a n 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 s timulation of GH was determined to be 485 ng/ml. The proposed indirect-resp onse model requiring a threshold concentration and development of tolerance provided a useful mean of quantifying the effects of NN703. Furthermore, t he development of tolerance shown based on pharmacokinetic/pharmacodynamic modeling of single-dose data presented here has been confirmed following mu ltiple dosing in healthy male subjects. (C) 2001 the American College of Cl inical Pharmacology.