Sweeney K R, Gastonguay M R, Benincosa L, Cronenberger C L, Glue P, Malhotra B K
Pfizer Inc., Groton, CT, USA;
Drug Discov Ther. 2010 Feb;4(1):44-53.
The objective of this analysis was to explore exposure-response modeling of data from a thorough QT (TQT) study of tolterodine in CYP2D6 extensive (EMs) and poor metabolizers (PMs). Crossover treatments of the TQT study included the recommended (2 mg twice daily) and supratherapeutic (4 mg twice daily) doses of tolterodine, moxifloxacin (400 mg once daily), and placebo. The concentration-response relationships for the QTc effects of moxifloxacin and tolterodine were described using a linear model with baseline effect, placebo effect, and a drug effect. The mixed effects modeling approach, using the first order conditional estimation method, was implemented in NONMEM. Simulated data from 250 trial replicates were used for limited predictive check and to describe the expected extreme responders in this study, under the derived model and point estimates. Modeling results for tolterodine showed linear concentrationdependent increases in QTc interval, with no difference in slopes between EMs and PMs. Modelpredicted QTc prolongations for tolterodine and moxifloxacin were consistent with their respective observed mean results. No subjects were predicted to have increases of > 60 milliseconds (ms); the predicted incidence of borderline QTc increases (> 30 and ≤ 60 ms) remained low at the supratherapeutic tolterodine dose in both PMs (9.1%) and EMs (3.9%). In conclusions, this analysis supports our clinical experience that tolterodine does not have a clinically significant effect on QT interval.
该分析的目的是探索托特罗定在CYP2D6基因的快代谢型（EMs）和慢代谢型（PMs）患者中的全面QT（TQT）研究数据的暴露-反应模型。TQT研究的交叉治疗包括推荐剂量（每日两次，每次2mg）和超治疗剂量（每日两次，每次4mg）的托特罗定、莫西沙星（每日一次，400mg）和安慰剂。使用具有基线效应、安慰剂效应和药物效应的线性模型来描述莫西沙星和托特罗定对QTc的浓度-反应关系。采用一阶条件估计法的混合效应建模方法在NONMEM中实施。来自250次试验重复的模拟数据用于有限预测检验，并根据推导模型和点估计描述本研究中预期的极端反应者。托特罗定的建模结果显示QTc间期呈线性浓度依赖性增加，EMs和PMs之间的斜率无差异。模型预测的托特罗定和莫西沙星的QTc延长与各自观察到的平均结果一致。预计没有受试者的QTc增加超过60毫秒（ms）；在超治疗剂量的托特罗定治疗下，PMs（9.1%）和EMs（3.9%）中QTc临界增加（>30且≤60ms）的预测发生率仍然较低。总之，该分析支持我们的临床经验，即托特罗定对QT间期没有临床显著影响。
