Advanced Modeling and Simulation, Clinical Pharmacology Division, Johnson & Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium.
J Clin Pharmacol. 2010 Mar;50(3):293-310. doi: 10.1177/0091270009346057. Epub 2010 Jan 7.
The time course of Positive and Negative Syndrome Scale (PANSS) scores in adult schizophrenia patients was modeled, and the effectiveness of paliperidone extended-release tablets (paliperidone ER) and olanzapine was quantified. Data from 3 randomized, double-blind phase III studies were used. Patients received paliperidone ER (3, 6, 9, 12, or 15 mg), olanzapine 10 mg, or matched placebo once daily for 6 consecutive weeks. An indirect response model implemented using a nonlinear mixed effects approach described the time course of the PANSS. Deterioration rate was modeled as a function of baseline PANSS score, placebo, and drug effects, and the dropout effect. An exponential decrease of the placebo response was also implemented. Paliperidone ER and olanzapine treatment were characterized by a long-lasting drug effect (13%), with a larger but short-lasting placebo effect (40%) and a notable dropout rate. The covariate exploration failed to identify any clinically relevant factors. The nonparametric bootstrap analysis confirmed the acceptable precision of parameter estimates. The visual predictive check supported the model's adequacy to reproduce observed PANSS time courses. The population model describes the time course of PANSS scores in schizophrenia patients and is appropriate for use in clinical trial simulation activities.
对成人精神分裂症患者阳性与阴性症状量表（PANSS）评分的时间过程进行建模，并定量评估帕利哌酮长效片（paliperidone ER）和奥氮平的疗效。使用了 3 项随机、双盲 III 期研究的数据。患者接受帕利哌酮 ER（3、6、9、12 或 15mg）、奥氮平 10mg 或匹配的安慰剂，每日 1 次，连续 6 周。采用非线性混合效应方法实现的间接响应模型描述了 PANSS 的时间过程。恶化率被建模为基线 PANSS 评分、安慰剂和药物效应以及脱落效应的函数。还实施了安慰剂反应的指数下降。帕利哌酮 ER 和奥氮平治疗的特点是具有持久的药物效应（13%），但具有更大但短暂的安慰剂效应（40%）和明显的脱落率。协变量探索未能确定任何临床相关因素。非参数自举分析证实参数估计具有可接受的精度。直观预测检查支持模型充分再现观察到的 PANSS 时间过程。该群体模型描述了精神分裂症患者 PANSS 评分的时间过程，适合用于临床试验模拟活动。
