摘要
为明确控释(CR)剂型卡维地洛1次/d是否提供了与目前市场销售的速释(IR)剂型2次/d相似的24hβ1-受体阻滞作用,对自行车测力试验后运动诱导的心率变化进行检测。
To determine whether the controlled-release (CR) formulation of carvedilol given once daily provides 24-hour β_1-receptor blockade similar to the currently marketed immediate-release (IR) formulation given twice daily, changes in exercise-induced heart rate after bicycle ergometry were measured. The pharmacokinetic (PK)/pharmacodynamic (PD) relation between S(-) carvedilol concentration-the enantiomer with β-blocking activity-and change in exercise-induced heart rate was defined in healthy subjects and was best described using a direct effect inhibitory Emax model (with Emax being the maximum effect). The population estimates for Emax and concentration at 50%of the maximum effect (EC50) were 19.2 beats per minute (an approximately 13%maximum decrease in exercise-induced heart rate) and 7.7 ng/mL, respectively. The PK/PD model was used to predict PD effects in patients with mild-to-severe heart failure and in patients after myocardial infarction with left ventricular dysfunction who had received both the IR and CR formulations of carvedilol. In these patients, carvedilol CR had equivalent predicted overall PD (area under the effect curve) and trough (PDmin) effects compared with carvedilol IR, indicating 24-hour β-blocking coverage for the new CR formulation of carvedilol given once daily.
