Chapel Sunny, Chiu Yu-Yuan, Hsu Jay, Cucchiaro Josephine, Loebel Antony
Ann Arbor Pharmacometrics Group Inc, Ann Arbor, Michigan.
Sunovion Pharmaceuticals Inc, Fort Lee, New Jersey.
Clin Ther. 2016 Jan 1;38(1):4-15. doi: 10.1016/j.clinthera.2015.11.013. Epub 2015 Dec 22.
Characterization of dose-response relationships for psychotropic agents may be difficult to determine based on results of individual clinical studies, particularly those with a flexible dose design. The goal of this pharmacometric analysis was to characterize the dose-response profile for lurasidone in patients with bipolar depression.
The statistical modeling and simulation analyses reported here were derived from 2 randomized, 6-week, double-blind, placebo-controlled, flexible-dose studies (20-60 mg/d or 80-120 mg/d of lurasidone as monotherapy or 20-120 mg/d adjunct to lithium or valproate) in patients with bipolar depression. Pooled data included 5245 Montgomery-Åsberg Depression Rating Scale (MADRS) observations from 825 patients who had received lurasidone or placebo treatments, with or without lithium or valproate background medication.
The time course of placebo effect on the MADRS score was adequately described by an exponential asymptotic placebo model. A linear dose-response model best described the effect of lurasidone. The net improvement in MADRS score due to lurasidone treatment (the drug effect) was significant (P < 0.001), and a positive dose response was detected. Net drug effect after 6 weeks of treatment was estimated to be a 6.0-point decrease in MADRS score per 100 mg of lurasidone. Covariate effects (for age and lithium or valproate use) were significant only for placebo effect parameters; thus, no dose adjustment was necessary related to demographic covariates.
This population dose-response modeling analysis indicates that higher doses of lurasidone are likely to produce greater therapeutic effects in patients with bipolar depression. The linear dose response was consistent for both lurasidone monotherapy and adjunctive therapy in patients with bipolar depression. ClinicalTrials.gov identifiers: NCT00868452, NCT00868699.
基于个体临床研究结果，尤其是那些采用灵活剂量设计的研究，可能难以确定精神药物的剂量-反应关系。本药物计量学分析的目的是描述鲁拉西酮治疗双相抑郁患者的剂量-反应特征。
此处报告的统计建模和模拟分析源自2项随机、为期6周、双盲、安慰剂对照、灵活剂量研究（鲁拉西酮单药治疗剂量为20 - 60 mg/d或80 - 120 mg/d，或作为锂盐或丙戊酸盐的辅助治疗剂量为20 - 120 mg/d），研究对象为双相抑郁患者。汇总数据包括来自825例接受鲁拉西酮或安慰剂治疗的患者的5245次蒙哥马利-Åsberg抑郁评定量表（MADRS）观察结果，这些患者使用或未使用锂盐或丙戊酸盐作为背景药物。
指数渐近安慰剂模型充分描述了安慰剂对MADRS评分的时间进程影响。线性剂量-反应模型最能描述鲁拉西酮的效应。鲁拉西酮治疗导致的MADRS评分净改善（药物效应）显著（P < 0.001），且检测到正性剂量反应。治疗6周后的净药物效应估计为每100 mg鲁拉西酮使MADRS评分降低6.0分。协变量效应（年龄以及使用锂盐或丙戊酸盐）仅对安慰剂效应参数有显著影响；因此，无需根据人口统计学协变量进行剂量调整。
该群体剂量-反应建模分析表明，较高剂量的鲁拉西酮可能对双相抑郁患者产生更大的治疗效果。在双相抑郁患者中，鲁拉西酮单药治疗和辅助治疗的线性剂量反应是一致的。ClinicalTrials.gov标识符：NCT00868452，NCT00868699。
