Agersø H, Ynddal L, Søgaard B, Zdravkovic M
Department of Pharmacokinetics, Novo Nordisk A/S, Novo Nordisk Park, 2760 Maaloev, Denmark.
J Clin Pharmacol. 2001 Feb;41(2):163-9. 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.
本研究的目的是描述生长激素（GH）释放促分泌素NN703在口服给予健康男性受试者后的药代动力学和药效学。该研究设计为一项随机、安慰剂对照、双盲、剂量递增的单剂量NN703试验，涵盖八个剂量水平。每个剂量水平有6名受试者接受活性治疗，2名受试者接受安慰剂治疗。NN703以溶液形式口服给药。在给药前和给药后长达24小时采集血样，用于检测NN703和GH的血清浓度。基于固相萃取和LC/MS/MS检测，使用经过验证的分析方法测定NN703的血清浓度。采用具有零级输入的二室模型描述NN703的药代动力学。同时拟合消除相参数，而描述吸收相的参数在不同剂量水平之间允许变化。通过使用包含阈值和耐受性发展调节剂的间接反应模型描述NN703的药效学。得出结论，口服给药后NN703的吸收是非线性的；生物利用度随剂量增加。确定刺激GH达到最大反应一半时所需的NN703血清浓度为485 ng/ml。所提出的需要阈值浓度和耐受性发展的间接反应模型为量化NN703的效应提供了一种有用的方法。此外，此处基于单剂量数据的药代动力学/药效学建模显示的耐受性发展在健康男性受试者多次给药后得到了证实。
