Grasela T H, Antal E J, Ereshefsky L, Wells B G, Evans R L, Smith R B
Pharmacokinetic/Pharmacodynamic Research Unit, Upjohn Company, Kalamazoo, MI 49001.
Clin Pharmacol Ther. 1987 Oct;42(4):433-41. doi: 10.1038/clpt.1987.174.
The use of observational data, collected during the routine clinical care of patients, has been advocated as a means to obtain clinically relevant information regarding the pharmacokinetic parameters of drugs. However, the validity of this approach and its proper role in new drug development is unclear. This study was performed to evaluate the ability of three approaches to estimate population pharmacokinetic parameters: the traditional approach, mixed-effect modeling, and a simple pharmacokinetic screen. The evaluation was performed with data collected during a multicenter, open-label study evaluating the efficacy, safety, and pharmacokinetics of imipramine and alprazolam in combination. The traditional pharmacokinetic study demonstrated a 20% decrease in the clearance of imipramine in the presence of 4 mg/day alprazolam. Mixed-effect modeling extends these findings by suggesting that the interaction is dependent on the simultaneous concentration of alprazolam, a finding that was not possible under the study design typically used for traditional pharmacokinetic studies. Although the simple screen suggests the presence of the drug-drug interaction, limited information regarding pharmacokinetic parameters is available and those parameters that can be estimated are biased.
在患者常规临床护理过程中收集观察数据，已被提倡作为获取有关药物药代动力学参数的临床相关信息的一种手段。然而，这种方法的有效性及其在新药开发中的适当作用尚不清楚。本研究旨在评估三种估计群体药代动力学参数的方法的能力：传统方法、混合效应建模和简单药代动力学筛选。评估是使用在一项多中心、开放标签研究中收集的数据进行的，该研究评估了丙咪嗪和阿普唑仑联合使用的疗效、安全性和药代动力学。传统药代动力学研究表明，在阿普唑仑剂量为4毫克/天时，丙咪嗪的清除率降低了20%。混合效应建模扩展了这些发现，表明这种相互作用取决于阿普唑仑的同时浓度，这一发现在传统药代动力学研究通常使用的研究设计下是不可能的。尽管简单筛选表明存在药物相互作用，但有关药代动力学参数的信息有限，且能够估计的那些参数存在偏差。
