Le Coz F, Funck-Brentano C, Morell T, Ghadanfar M M, Jaillon P
Clinical Pharmacology Unit, Saint-Antoine University Hospital, Paris, France.
Clin Pharmacol Ther. 1995 May;57(5):533-42. doi: 10.1016/0009-9236(95)90038-1.
To examine the pharmacokinetics and the relation between plasma concentrations of the new potassium channel blocker dofetilide and QTc prolongation on the surface electrocardiogram after oral and intravenous administration.
Ten healthy volunteers received a single dose of 0.5 mg dofetilide orally and intravenously (over 30 minutes) in a randomized crossover study. The QTc interval versus dofetilide plasma concentration was analyzed by use of pharmacokinetic and pharmacodynamic modeling techniques.
Dofetilide absolute bioavailability and systemic clearance were 92% +/- 9% and 0.35 +/- 0.05 L/hr/kg, respectively. Mean maximum increase in QTc interval duration was 99 msec (27%) and 61 msec (16%) after intravenous and oral administration, respectively. A counterclockwise hysteresis loop between dofetilide plasma concentrations and QTc interval duration was observed after intravenous infusions in all subjects, whereas direct linear relationships were observed after oral administrations in eight of 10 subjects. Pharmacokinetic-pharmacodynamic modeling showed the consistency of the effect versus concentration relationships obtained with the two routes of administration. With use of a maximum effect (Emax) model and data obtained after intravenous infusion, mean maximum QTc prolongation (Emax) was 121 +/- 57 msec and mean dofetilide plasma concentration associated with half the maximum effect (EC50) was 2.2 +/- 0.6 ng/ml. Pharmacokinetic-pharmacodynamic modeling was useful in detecting the maximum effect and in describing the plasma concentration versus effect relationship during intravenous infusion of dofetilide but was otherwise not superior to analyses performed with postdistribution data.
We conclude that dofetilide prolongs QTc interval duration in a concentration-dependent manner in normal volunteers during sinus rhythm and that pharmacokinetic-pharmacodynamic modeling is useful for examination of maximum QTc prolongation induced by dofetilide.
研究新型钾通道阻滞剂多非利特口服和静脉给药后的药代动力学，以及其血药浓度与体表心电图QTc间期延长之间的关系。
在一项随机交叉研究中，10名健康志愿者分别接受了单次口服和静脉注射（30分钟内）0.5毫克多非利特。采用药代动力学和药效学建模技术分析QTc间期与多非利特血药浓度的关系。
多非利特的绝对生物利用度和全身清除率分别为92%±9%和0.35±0.05升/小时/千克。静脉注射和口服给药后，QTc间期持续时间的平均最大增加分别为99毫秒（27%）和61毫秒（16%）。所有受试者静脉输注后均观察到多非利特血药浓度与QTc间期持续时间之间呈逆时针滞后环，而10名受试者中有八名口服给药后观察到直接线性关系。药代动力学-药效学建模显示两种给药途径获得的效应与浓度关系具有一致性。使用最大效应（Emax）模型和静脉输注后获得的数据，平均最大QTc延长（Emax）为121±57毫秒，与最大效应一半相关的多非利特平均血药浓度（EC50）为2.2±0.6纳克/毫升。药代动力学-药效学建模有助于检测最大效应，并描述多非利特静脉输注期间血药浓度与效应的关系，但在其他方面并不优于使用分布后数据进行的分析。
我们得出结论，在窦性心律的正常志愿者中，多非利特以浓度依赖的方式延长QTc间期持续时间，药代动力学-药效学建模有助于研究多非利特引起的最大QTc延长。
