Bies Robert R, Feng Yan, Lotrich Francis E, Kirshner Margaret A, Roose Steven, Kupfer David J, Pollock Bruce G
Department of Psychiatry and Pharmaceutical Sciences, University of Pittsburgh, 805 Salk Hall, 3501 Terrace Street, Pittsburgh, PA 15213, USA.
J Clin Pharmacol. 2004 Dec;44(12):1352-9. doi: 10.1177/0091270004269647.
The objective of this study was to evaluate whether the disposition of the selective serotonin reuptake inhibitor, citalopram, could be robustly captured using 1 to 2 concentration samples per subject in 106 patients participating in 2 clinical trials. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic parameters describing citalopram's disposition. Both a prior established 2-compartment model and a de novo 1-compartment pharmacokinetic model were used. Covariates assessed were concomitant medications, race, sex, age (22-93 years), and weight. Covariates affecting disposition were assessed separately and then combined in a stepwise manner. Pharmacokinetic characteristics of citalopram were well captured using this sparse sampling design. Two covariates (age and weight) had a significant effect on the clearance and volume of distribution in both the 1- and 2-compartment pharmacokinetic models. Clearance decreased 0.23 L/h for every year of age and increased 0.14 L/h per kilogram body weight. It was concluded that hyper-sparse sampling designs are adequate to support population pharmacokinetic analysis in clinically treated populations. This is particularly valuable for populations such as the elderly, who are not typically available for pharmacokinetic studies.
本研究的目的是评估在参与两项临床试验的106名患者中，每名受试者采集1至2个血药浓度样本，能否充分获取选择性5-羟色胺再摄取抑制剂西酞普兰的处置情况。采用非线性混合效应模型评估描述西酞普兰处置情况的药代动力学参数。使用了一个先前建立的二室模型和一个全新的一室药代动力学模型。评估的协变量包括合并用药、种族、性别、年龄（22至93岁）和体重。分别评估影响处置的协变量，然后逐步合并。使用这种稀疏采样设计能够很好地获取西酞普兰的药代动力学特征。在一室和二室药代动力学模型中，两个协变量（年龄和体重）对清除率和分布容积均有显著影响。清除率随年龄每年降低0.23 L/h，随体重每千克增加0.14 L/h。得出的结论是，超稀疏采样设计足以支持临床治疗人群的群体药代动力学分析。这对于像老年人这类通常无法参与药代动力学研究的人群尤为有价值。
