Ragueneau I, Laveille C, Jochemsen R, Resplandy G, Funck-Brentano C, Jaillon P
Clinical Pharmacology Unit, Saint-Antoine University Hospital, Paris, France.
Clin Pharmacol Ther. 1998 Aug;64(2):192-203. doi: 10.1016/S0009-9236(98)90153-9.
Ivabradine (S-16257) is a new bradycardic agent with a direct effect on the sinus node. Its N-dealkylated metabolite, S-18982, has shown a bradycardic activity in animals. The aim of this trial was to study the correlation between drug bradycardic activity and plasma levels of the parent compound and its metabolite in healthy volunteers.
Eighteen healthy volunteers participated in three successive study periods: an oral double-blind period with two parallel groups of doses (10 or 20 mg, single and repeated); a 10 mg intravenous bolus open period; and a final control period. The effects of ivabradine on heart rate were studied at rest and during bicycle exercise tests (at 85% of maximum workload) during 24-hour postdosing, and ivabradine and S-18982 plasma levels were determined simultaneously.
The maximal reductions of exercise heart rate were 11% +/- 4% (10 mg) and 18% +/- 6% (20 mg) after single oral doses (p < 0.05) and 18% +/- 4% (10 mg) and 27% +/- 6% (20 mg) after repeated doses (p < 0.01). Maximum heart rate reduction after the intravenous bolus was 19% +/- 4%. After oral administrations an indirect relationship between the bradycardic effect and the plasma concentrations of the two compounds was found. A pharmacokinetic/pharmacodynamic population analysis done with the NONMEM computer program showed that S-18982 contributes in part to the overall activity of ivabradine: modeling suggested that the metabolite is responsible for the initial bradycardic effect, whereas the parent compound is responsible for the duration of action.
This study shows that ivabradine exerts a dose-dependent bradycardic effect and that its N-dealkylated metabolite contributes to this bradycardic effect.
伊伐布雷定（S - 16257）是一种对窦房结有直接作用的新型降心率药物。其N - 去烷基代谢产物S - 18982在动物实验中已显示出降心率活性。本试验旨在研究健康志愿者中药物降心率活性与母体化合物及其代谢产物血浆水平之间的相关性。
18名健康志愿者参与了三个连续的研究阶段：一个口服双盲阶段，分为两个平行剂量组（10或20毫克，单次和重复给药）；一个10毫克静脉推注的开放阶段；以及最后一个对照阶段。在给药后24小时内，于静息状态和自行车运动试验（最大工作量的85%）期间研究伊伐布雷定对心率的影响，并同时测定伊伐布雷定和S - 18982的血浆水平。
单次口服给药后，运动心率的最大降幅在10毫克组为11%±4%，20毫克组为18%±6%（p < 0.05）；重复给药后，1日毫克组为18%±4%，20毫克组为27%±6%（p < 0.01）。静脉推注后的最大心率降幅为19%±4%。口服给药后，发现降心率效应与两种化合物的血浆浓度之间存在间接关系。使用NONMEM计算机程序进行的药代动力学/药效学群体分析表明，S - 18982部分促成了伊伐布雷定的总体活性：模型显示，代谢产物负责初始降心率效应，而母体化合物负责作用持续时间。
本研究表明，伊伐布雷定具有剂量依赖性的降心率作用，其N - 去烷基代谢产物促成了这种降心率作用。
