Allen M J, Nichols D J, Oliver S D
Pfizer Central Research, Sandwich, Kent, UK.
Br J Clin Pharmacol. 2000 Sep;50(3):247-53. doi: 10.1046/j.1365-2125.2000.00243.x.
The pharmacokinetics and pharmacodynamics of oral dofetilide, a novel, class III antiarrhythmic drug, were assessed during administration either twice or three times daily.
Dofetilide was administered orally to three groups of healthy subjects in daily doses of 1000 microg (n = 8), 1500 microg (n = 8), or 2500 microg (n = 9) as twice daily and three times daily treatment regimens, with the two regimens assigned randomly as a two-way crossover for each subject and separated by at least a 6 day washout period.
Pharmacokinetic analysis indicated a rise in plasma dofetilide concentrations until steady state was attained on day 3. Ctrough had a linear dependence on dose for both the twice daily and three times daily dosing regimens. The maximum concentration attained (Cmax) and the area under the concentration vs time curve (AUC(0,tau) increased linearly with dose for each dosing regimen on both days 1 and 5 of dosing. Cmax occurred at 2 h. Pharmacodynamic measurements showed that the QTc interval increased in a dose-dependent manner and that the time to maximum QTc was 2 h after dosing. A linear relationship was determined between plasma dofetilide concentration and the prolongation of the QTc interval. The slope of this line was significantly greater on day 1 (ranging from 12.9 to 14.2 ms/ng ml-1) than on day 5 (ranging from 9.9 to 12. 8 ms/ng ml(-1).
The pharmacokinetics and pharmacodynamics of dofetilide are predictable and based on a linear relationship for both twice daily and three times daily dosing regimens. The QT responsiveness to dofetilide is greater on day 1 than on day 5.
评估新型Ⅲ类抗心律失常药物口服多非利特每日给药两次或三次时的药代动力学和药效学。
将多非利特口服给予三组健康受试者，每日剂量分别为1000微克（n = 8）、1500微克（n = 8）或2500微克（n = 9），采用每日两次和每日三次的治疗方案，两种方案随机分配给每个受试者作为双向交叉设计，且至少间隔6天的洗脱期。
药代动力学分析表明，直到第3天达到稳态之前，血浆多非利特浓度呈上升趋势。每日两次和每日三次给药方案的谷浓度（Ctrough）均与剂量呈线性相关。给药第1天和第5天，每种给药方案的最大浓度（Cmax）和浓度-时间曲线下面积（AUC(0,tau)）均随剂量呈线性增加。Cmax出现在给药后2小时。药效学测量表明，QTc间期呈剂量依赖性增加，最大QTc出现时间为给药后2小时。确定了血浆多非利特浓度与QTc间期延长之间的线性关系。该直线斜率在第1天（范围为12.9至14.2毫秒/纳克·毫升-1）显著大于第5天（范围为9.9至12.8毫秒/纳克·毫升-1）。
多非利特的药代动力学和药效学是可预测的，且基于每日两次和每日三次给药方案的线性关系。多非利特在第1天的QT反应性大于第5天。
