A generic kinetic-pharmacodynamic (K-PD) model to describe the response to treatment assessed by a clinical score for depressed patients treated by antidepressants alone or combined with a drug that shortens the lag-time before effect was developed. The aims of this study were: (1) to verify model's ability to characterize clinical data, (2) to evaluate several statistics to summarize the clinical effect, (3) to compare the analysis based on these statistics to the conventional intent-to-treat analysis and (4) to determine the optimal dates of clinical assessment. The population K-PD model was fitted to the individual data from a randomized clinical trial assessing the efficacies of clomipramine and placebo or clomipramine and lithium to treat major depression in 141 patients. The K-PD model was able to fit the individual data even in the case of oscillating score profiles. The interindividual coefficient of variation of the model parameters ranged from 33 to 161%. The statistical analysis based on the secondary parameters yielded conclusions comparable to those of the conventional intent-to-treat analysis. The population model was then used for a clinical trial simulation. According to the simulation, the most sensitive summary statistics for detecting a difference between lithium and placebo were the fractional reduction of depression and the proportion of responders. The optimal dates to assess these parameters were day 9 and 11 respectively. The K-PD model might serve as a tool for clinical trial planning in the field of research on antidepressants and their facilitators.

译文

通用动力学-药效学 (k-pd) 模型,用于描述通过临床评分评估的抑郁症患者对治疗的反应,该抑郁症患者单独使用抗抑郁药或与药物联合使用可缩短效果产生前的滞后时间。本研究的目的是 :( 1) 验证模型表征临床数据的能力,(2) 评估几种统计数据以总结临床效果,(3) 将基于这些统计数据的分析与常规意向治疗分析进行比较,以及 (4) 确定临床评估的最佳日期。将人群k-pd模型拟合到一项随机临床试验的个体数据,该试验评估了氯米帕明和安慰剂或氯米帕明和锂治疗141例患者重度抑郁症的疗效。即使在分数分布振荡的情况下,k-pd模型也能够拟合单个数据。模型参数的个体间变异系数为33 ~ 161%。基于次要参数的统计分析得出的结论与常规意向治疗分析的结论相当。然后将人口模型用于临床试验模拟。根据模拟,检测锂和安慰剂之间差异的最敏感的汇总统计数据是抑郁症的分数减少和响应者的比例。评估这些参数的最佳日期分别是第9天和第11天。K-pd模型可以作为抗抑郁药及其促进剂研究领域的临床试验计划的工具。

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