Kisicki James C, Fiske Kimberly, Lyne Andrew
MDS Pharma Services, Lincoln, Nebraska 68502, USA.
Clin Ther. 2007 Sep;29(9):1967-79. doi: 10.1016/j.clinthera.2007.09.020.
Guanfacine hydrochloride is an alpha(2a)-adrenoreceptor agonist found to be effective in the treatment of attention-deficit/hyperactivity disorder (ADHD). Because the available immediate-release formulation requires multiple daily dosing and has been associated with rebound hypertension on abrupt cessation, an extended-release (ER) formulation has been developed for study of efficacy and tolerability parameters in patients with ADHD.
This trial was primarily undertaken to determine the effect on blood pressure (BP) of abrupt cessation versus taper-down of guanfacine ER.
This Phase I, randomized, double-blind, placebo-controlled, dose-escalation trial was conducted at MDS Pharma Services, Lincoln, Nebraska. Male and female healthy young-adult (aged 19-24 years) volunteers were included. Subjects were randomly assigned to receive guanfacine ER as follows. Abrupt-cessation and taper-down groups both received guanfacine ER at forced titration: 1 mg on days 1 to 4, 2 mg on days 5 to 8, 3 mg on days 9 to 12, and 4 mg on days 13 to 16. The abrupt-cessation group then received placebo daily on days 17 to 32. The taper-down group began the following taper-down schedule: 3 mg on days 17 to 20, 2 mg on days 21 to 24, 1 mg on days 25 to 30, and placebo on days 31 to 32. Placebo was administered daily to the subjects in the placebo group (days 1-32). All doses were given in the morning. Tolerability was assessed before (at the 8-hour baseline visit), during (approximately every 4 days and during 48-hour confinements at days 17/18 and 31/32), and 7 days after the study and included assessment of BP and pulse, 12-lead electrocardiography (ECG), and laboratory assays. Adverse events (AEs) were also tracked every 4 days beginning on day 5 and 7, 14, and 30 days poststudy by recording responses and follow-up to a nonleading question about how the patient was feeling that day.
Forty-five subjects were enrolled in the study (15 in each group), and 35 subjects completed it. The mean age of study participants was 22 years, 87% were white, and the ratio of women to men was 2:1. There were no marked differences between groups regarding age, sex, or race. Compared with the taperdown group, the abrupt-cessation group did not exhibit a clinically significant elevation of systolic BP (SBP) or diastolic BP (DBP) or other tolerability parameters, including AEs. Significant differences in BP were observed on days 17/18 (first day of abrupt cessation) and 31/32, but the overall means were not statistically different. The SBP decreases were -7.55% (-8.84 mm Hg) in the abrupt-cessation group and -8.33% (-9.69 mm Hg) in the taper-down group. The DBP decreases were -9.14% (-6.17 mm Hg) in the abrupt-cessation group and -9.94% (-6.59 mm Hg) in the taper-down group. There were no statistically significant or clinically important differences in change or percentage change in pulse from baseline to day 31/32 between the taper-down and placebo groups (least squares mean difference, 2.26 bpm). None of the subjects experienced bradycardia. No clinically important treatment related trends were noted in the clinical laboratory, ECG, or physical examination findings, including vital signs. No serious treatment-emergent AEs were reported in this study. Overall, 124 treatment-emergent AEs were reported in 29 (64%) subjects. Treatment-emergent AEs were reported in 14 (93.3%) of 15 subjects in the abrupt-cessation group, 8 (53.3%) of 15 subjects in the taper-down group, and 7 (46.7%) of 15 subjects in the placebo group. Headache was the most common AE reported in the abrupt-cessation (46.7%) and placebo (13.3%) groups. For the taper down group, it was dry mouth (26.7%). All AEs were classified as mild or moderate.
In this small study group of healthy, young-adult volunteers, guanfacine ER at doses up to 4 mg/d was abruptly discontinued without significant increases in SBP or DBP or other tolerability parameters, including AEs, compared with taper.
盐酸胍法辛是一种α（2a）-肾上腺素能受体激动剂，已被发现对治疗注意力缺陷多动障碍（ADHD）有效。由于现有的速释制剂需要每日多次给药，且突然停药会导致反弹性高血压，因此已开发出一种缓释（ER）制剂，用于研究ADHD患者的疗效和耐受性参数。
本试验主要旨在确定突然停药与逐渐减量停用胍法辛ER对血压（BP）的影响。
本I期随机、双盲、安慰剂对照、剂量递增试验在内布拉斯加州林肯市的MDS制药服务公司进行。纳入了健康的年轻成年（19 - 24岁）男性和女性志愿者。受试者被随机分配接受如下胍法辛ER治疗。突然停药组和逐渐减量组在强制滴定阶段均接受胍法辛ER：第1至4天为1 mg，第5至8天为2 mg，第9至12天为3 mg，第13至16天为4 mg。然后突然停药组在第17至32天每天接受安慰剂。逐渐减量组开始如下逐渐减量方案：第17至20天为3 mg，第21至24天为2 mg，第25至30天为1 mg，第31至32天为安慰剂。安慰剂组受试者在第1至32天每天服用安慰剂。所有剂量均在早晨给药。在研究前（8小时基线访视时）、研究期间（大约每4天以及在第17/18天和第31/32天的48小时限制期内）以及研究后7天评估耐受性，包括评估血压和脉搏、12导联心电图（ECG）以及实验室检测。从第5天开始每4天跟踪不良事件（AE），并在研究后第7天、14天和30天通过记录对关于患者当天感觉的非引导性问题的回答和随访来跟踪。
45名受试者参与了该研究（每组15名），35名受试者完成了研究。研究参与者的平均年龄为22岁，87%为白人，女性与男性的比例为2:1。各组在年龄、性别或种族方面无明显差异。与逐渐减量组相比，突然停药组未出现收缩压（SBP）或舒张压（DBP）的临床显著升高或其他耐受性参数升高，包括不良事件。在第17/18天（突然停药的第一天）和第31/32天观察到血压有显著差异，但总体平均值无统计学差异。突然停药组的SBP下降为-7.55%（-8.84 mmHg），逐渐减量组为-8.33%（-9.69 mmHg）。突然停药组的DBP下降为-9.14%（-6.17 mmHg），逐渐减量组为-9.94%（-6.59 mmHg）。逐渐减量组与安慰剂组从基线到第31/32天脉搏变化或变化百分比无统计学显著或临床重要差异（最小二乘平均差异，2.26次/分钟）。没有受试者出现心动过缓。在临床实验室、ECG或体格检查结果（包括生命体征）中未观察到与治疗相关的临床重要趋势。本研究未报告严重的治疗突发不良事件。总体而言，29名（64%）受试者报告了124次治疗突发不良事件。突然停药组15名受试者中有14名（93.3%）报告了治疗突发不良事件，逐渐减量组15名受试者中有8名（53.3%），安慰剂组15名受试者中有7名（46.7%）。头痛是突然停药组（46.7%）和安慰剂组（13.3%）报告的最常见不良事件。对于逐渐减量组，是口干（26.7%）。所有不良事件均分类为轻度或中度。
在这个由健康年轻成年志愿者组成的小研究组中，与逐渐减量相比，突然停用高达4 mg/d剂量的胍法辛ER未导致SBP或DBP或其他耐受性参数（包括不良事件）显著增加。
