González-Sales Mario, Barrière Olivier, Tremblay Pierre Olivier, Nekka Fahima, Mamputu Jean-Claude, Boudreault Sylvie, Tanguay Mario
Université de Montréal, Montreal, Canada.
J Pharmacokinet Pharmacodyn. 2015 Jun;42(3):287-99. doi: 10.1007/s10928-015-9416-2. Epub 2015 Apr 21.
The objective of this analysis was to characterize the time course of selected pharmacodynamic (PD) markers of tesamorelin: growth hormone (GH) and insulin-like growth factor (IGF-1) concentrations in HIV-infected patients and healthy volunteers. A total of 41 subjects in Phase I trials receiving subcutaneous daily doses of 1 or 2 mg of tesamorelin during 14 consecutive days were included in this analysis. A previous pharmacokinetic (PK) model of tesamorelin was used as the input function for the PD model of GH. Tesamorelin was hypothesized to stimulate the secretion of GH in an "episodic" manner, i.e., for a finite duration of time. The resulting PK/PD model of GH was used to describe the time course of IGF-1. The effect of age, body weight, body mass index, sex, race, and health status on the model parameters was evaluated. The model was qualified using predictive checks and non-parametric bootstrap. Within the range of the values evaluated no covariates were significantly associated with GH or IGF-1 model parameters. Model evaluation procedures indicated accurate prediction of the selected pharmacodynamic markers. The time course of GH and IGF-1 concentrations following multiple doses of tesamorelin were well predicted by the sequential PK/PD model developed using Phase I data.
本分析的目的是描述替莫瑞林特定药效学（PD）标志物的时间进程：HIV感染患者和健康志愿者体内生长激素（GH）和胰岛素样生长因子（IGF-1）的浓度。本分析纳入了41名在I期试验中连续14天每日皮下注射1或2 mg替莫瑞林的受试者。替莫瑞林先前的药代动力学（PK）模型被用作GH的PD模型的输入函数。假设替莫瑞林以“间歇性”方式刺激GH分泌，即持续有限的时间。由此产生的GH的PK/PD模型用于描述IGF-1的时间进程。评估了年龄、体重、体重指数、性别、种族和健康状况对模型参数的影响。该模型通过预测检验和非参数自助法进行验证。在评估值范围内，没有协变量与GH或IGF-1模型参数显著相关。模型评估程序表明对所选药效学标志物的预测准确。使用I期数据开发的序贯PK/PD模型能很好地预测多次给予替莫瑞林后GH和IGF-1浓度的时间进程。
