卡维地洛缓释制剂的剂量比例关系和药代动力学：一项单剂量递增的10序列不完全区组研究。
Dose proportionality and pharmacokinetics of carvedilol sustained-release formulation: a single dose-ascending 10-sequence incomplete block study.
作者信息
Kim Yo Han, Choi Hee Youn, Noh Yook-Hwan, Lee Shi Hyang, Lim Hyeong-Seok, Kim Chin, Bae Kyun-Seop
机构信息
Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Republic of Korea.
Chong Kun Dang Clinical Research and Clinical Epidemiology and Medical Information, CKD Pharmaceuticals, Seoul, Republic of Korea.
出版信息
Drug Des Devel Ther. 2015 Jun 8;9:2911-8. doi: 10.2147/DDDT.S86168. eCollection 2015.
BACKGROUND
Carvedilol is a third-generation β-blocker indicated for congestive heart failure and high blood pressure. The aim of this study was to investigate the dose proportionality of the carvedilol sustained-release (SR) formulation in healthy male subjects.
METHODS
An open-label, single dose-ascending, 10-sequence, 3-period balanced incomplete block study was performed using healthy male subjects. In varying sequences, each subject received three of five carvedilol SR formulations (8, 16, 32, 64, or 128 mg once). The treatment periods were separated by a washout period of 7 days. Serial blood samples were collected up to 48 h after dosing. The plasma concentrations of carvedilol were determined by using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters including the area under the plasma concentration-time curve (AUC) from time 0 to the last measurable time (AUClast), AUC extrapolated to infinity (AUCinf), and the measured peak plasma concentration (C max) were obtained by noncompartmental analysis. Dose proportionality was evaluated if the ln-ln plots of AUClast, AUCinf, and C max versus dose were linear and the 90% confidence intervals (CIs) of the slopes were within 0.9195 and 1.0805. Tolerability was assessed by vital signs, electrocardiogram, clinical laboratory tests, and monitoring of adverse events (AEs) throughout the study.
RESULTS
A total of 31 subjects were enrolled, and 30 completed the study. The assessment of dose proportionality meets the statistical criteria; the point estimates of slope were 1.0104 (90% CI: 0.9849-1.0359) for AUClast, 1.0003 (90% CI: 0.9748-1.0258) for AUCinf, and 0.9901 (90% CI: 0.9524-1.0277) for C max, respectively. All AEs were mild, and none of the subjects dropped out due to AEs.
CONCLUSION
In this study, exposure to carvedilol was proportional over the therapeutic dose range of 8-128 mg. The carvedilol SR formulation was well tolerated.
背景
卡维地洛是一种第三代β受体阻滞剂，适用于充血性心力衰竭和高血压。本研究的目的是调查卡维地洛缓释（SR）制剂在健康男性受试者中的剂量比例关系。
方法
采用健康男性受试者进行了一项开放标签、单剂量递增、10序列、3周期平衡不完全区组研究。按照不同序列，每位受试者接受五种卡维地洛SR制剂中的三种（8、16、32、64或128mg，每日一次）。治疗周期之间间隔7天的洗脱期。给药后长达48小时采集系列血样。采用经过验证的液相色谱-串联质谱法测定卡维地洛的血浆浓度。通过非房室分析获得药代动力学参数，包括从0时间到最后可测量时间的血浆浓度-时间曲线下面积（AUClast）、外推至无穷大的AUC（AUCinf）以及实测的血浆峰浓度（Cmax）。如果AUClast、AUCinf和Cmax相对于剂量的ln-ln图呈线性，且斜率的90%置信区间（CI）在0.9195至1.0805之间，则评估剂量比例关系。在整个研究过程中，通过生命体征、心电图、临床实验室检查以及不良事件（AE）监测来评估耐受性。
结果
共纳入31名受试者，30名完成了研究。剂量比例关系评估符合统计学标准；AUClast的斜率点估计值为1.0104（90%CI：0.9849-1.0359），AUCinf为1.0003（90%CI：0.9748-1.0258），Cmax为0.9901（90%CI：0.9524-1.0277）。所有AE均为轻度，且无受试者因AE退出研究。
结论
在本研究中，在8-128mg的治疗剂量范围内，卡维地洛的暴露量呈比例关系。卡维地洛SR制剂耐受性良好。
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