Feng Yan, Pollock Bruce G, Coley Kim, Marder Stephen, Miller Del, Kirshner Margaret, Aravagiri Manickam, Schneider Lon, Bies Robert R
Strategic Modeling and Simulation Group, Bristol-Myers Squibb Co., Princeton, NJ, USA.
Br J Clin Pharmacol. 2008 Nov;66(5):629-39. doi: 10.1111/j.1365-2125.2008.03276.x. Epub 2008 Jul 31.
To characterize pharmacokinetic (PK) variability of risperidone and 9-OH risperidone using sparse sampling and to evaluate the effect of covariates on PK parameters.
PK analysis used plasma samples collected from the Clinical Antipsychotic Trials of Intervention Effectiveness. A nonlinear mixed-effects model was developed using NONMEM to describe simultaneously the risperidone and 9-OH risperidone concentration-time profile. Covariate effects on risperidone and 9-OH risperidone PK parameters were assessed, including age, weight, sex, smoking status, race and concomitant medications.
PK samples comprised 1236 risperidone and 1236 9-OH risperidone concentrations from 490 subjects that were available for analysis. Ages ranged from 18 to 93 years. Population PK submodels for both risperidone and 9-OH risperidone with first-order absorption were selected to describe the concentration-time profile of risperidone and 9-OH risperidone. A mixture model was incorporated with risperidone clearance (CL) separately estimated for three subpopulations [poor metabolizer (PM), extensive metabolizer (EM) and intermediate metabolizer (IM)]. Age significantly affected 9-OH risperidone clearance. Population parameter estimates for CL in PM, IM and EM were 12.9, 36 and 65.4 l h(-1) and parameter estimates for risperidone half-life in PM, IM and EM were 25, 8.5 and 4.7 h, respectively.
A one-compartment mixture model with first-order absorption adequately described the risperidone and 9-OH risperidone concentrations. Age was identified as a significant covariate on 9-OH risperidone clearance in this study.
采用稀疏采样法描述利培酮和9-羟基利培酮的药代动力学(PK)变异性,并评估协变量对PK参数的影响。
PK分析使用从临床抗精神病药物干预有效性试验中收集的血浆样本。使用NONMEM开发非线性混合效应模型,以同时描述利培酮和9-羟基利培酮的浓度-时间曲线。评估协变量对利培酮和9-羟基利培酮PK参数的影响,包括年龄、体重、性别、吸烟状况、种族和合并用药情况。
PK样本包括来自490名受试者的1236个利培酮浓度和1236个9-羟基利培酮浓度,可用于分析。年龄范围为18至93岁。选择具有一级吸收的利培酮和9-羟基利培酮的群体PK子模型来描述利培酮和9-羟基利培酮的浓度-时间曲线。采用混合模型,分别对三个亚组[慢代谢者(PM)、快代谢者(EM)和中间代谢者(IM)]单独估计利培酮清除率(CL)。年龄显著影响9-羟基利培酮的清除率。PM、IM和EM中CL的群体参数估计值分别为12.9、36和65.4 l h⁻¹,PM、IM和EM中利培酮半衰期的参数估计值分别为25、8.5和4.7 h。
具有一级吸收的单室混合模型能充分描述利培酮和9-羟基利培酮的浓度。在本研究中,年龄被确定为9-羟基利培酮清除率的显著协变量。