Duffull S B, Aarons L
School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.
Eur J Pharm Sci. 2000;10(4):275-84. doi: 10.1016/s0928-0987(00)00085-3.
Ivabradine is a novel bradycardic agent that has been developed for the prevention of angina. Ivabradine has an active metabolite S-18982. The aim of the study was to develop a linked pharmacokinetic-pharmacodynamic simulation model for the description of exercise-induced heart rate. The pharmacodynamic data (heart rate) were pooled from two studies and included a total of 78 healthy subjects. The data consisted of multiple dose oral administration of ivabradine. The multiple dose regimens were administered every 12 h. There were eight active dosing levels and placebo, and a no-dose run in the period before each study. The modelling was performed using the NONMEM software. Both ivabradine and S-18982 possess bradycardic activity, although the extent of the activity of both could not be determined from the data available. A multiple ligand pharmacodynamic model provided the best fit to the data. The model was assessed in terms of its posterior predictive performance and was able to describe the original data adequately when used for simulation purposes.
伊伐布雷定是一种新型的减慢心率药物，已被开发用于预防心绞痛。伊伐布雷定有一个活性代谢物S-18982。该研究的目的是建立一个药代动力学-药效学联合模拟模型，以描述运动诱发的心率。药效学数据（心率）来自两项研究，共纳入78名健康受试者。数据包括伊伐布雷定的多剂量口服给药。多剂量方案每12小时给药一次。有八个活性给药水平和安慰剂，且在每项研究前的时间段内有一个无剂量期。使用NONMEM软件进行建模。伊伐布雷定和S-18982均具有减慢心率的活性，尽管从现有数据中无法确定两者活性的程度。一个多配体药效学模型对数据拟合最佳。该模型根据其预测性能进行了评估，并且在用于模拟时能够充分描述原始数据。
