Swearingen Dennis, Pennick Michael, Shojaei Amir, Lyne Andrew, Fiske Kimberly
MDS Pharma Services, Phoenix, Arizona 85044, USA.
Clin Ther. 2007 Apr;29(4):617-25. doi: 10.1016/j.clinthera.2007.04.016.
Guanfacine is an alpha(2)-adrenoreceptor agonist used to treat children and adults with attention-deficit/hyperactivity disorder. An extended-release formulation of guanfacine is currently under development.
The objective of this study was to assess the single-dose pharmacokinetic properties and dose proportionality of guanfacine extended-release (GXR) tablets after oral administration in healthy adults.
This was a Phase I, randomized, open-label, single-dose, crossover trial of GXR 1-, 2-, and 4-mg tablets in healthy adults. In the lead-in period (period 1), subjects received a single GXR 1-mg tablet, and then were randomized to receive single GXR 2- or 4-mg tablets during 4 separate weekly visits. Vital signs were monitored, blood samples were obtained, and subjects underwent electrocardiography (ECG) before dose administration and at regular intervals over 96 hours. The pharmacokinetic parameters of CmaX, AUC(0-t), and AUC(0-infinity) were determined after each dose of GXR in all subjects. Summary statistics for the concentration-time data were analyzed to assess between-dose linearity. An analysis-of-variance model was constructed to test the concentration-time data for dose proportionality. Tolerability was assessed at each visit through the analysis of standard serology tests; urinalysis/drug screen reports; and physical examination, including height and weight measurements; vital-sign data; and ECG findings.
The total study enrollment was 52 subjects, including 28 men (53.8%) and 24 (46.2%) women. The subjects had a mean (SD) age of 32.9 (10.3) years (range, 18-54 years) and a mean (SD) body weight of 73.4 (15.7) kg (range, 49.6-120.0 kg). Forty (76.9%) subjects were Hispanic, 7 (13.5%) were white, and 5 (9.6%) were black. Three subjects were discontinued by the study investigators because of noncompliance with study procedures or use of concomitant medications. Forty-nine subjects completed the study. Mean (SD) values for guanfacine plasma concentrations with GXR 1, 2, and 4 mg, respectively, were 0.98 (0.26), 1.57 (0.51), and 3.58 (1.39) ng/mL for C(max); 29.3 (8.84), 54.5 (17.7), and 119.1 (42.3) ng/mL . h(-1) for AUC(0-t); and 32.4 (8.78), 58.0 (18.9), and 124.1 (45.1) ng/mL . h(-1) for AUC(0-infinity) . Mean (SD) t((1/2)) values were 17.5 (3.8), 16.6 (3.8), and 16.7 (4.90) hours for GXR 1, 2, and 4 mg, respectively. The geometric mean ratios for C(max), AUC(0-t), and AUC(0-infinity) were proportional to dose between GXR 1 and 2 mg, 1 and 4 mg, and 2 and 4 mg, except for the increase in C(max) between GXR 1 and 2 mg. All treatment-emergent adverse events (AEs) were assessed as mild or moderate and resolved without treatment with the exception of headache in 3 subjects and 1 case of lower back discomfort, which resolved with therapy. Left rib pain was reported in 1 subject, but it is unknown if it had resolved, since the subject was lost to followup. No subjects withdrew from participation or were discontinued by the study investigators as a result of AEs. The most common treatment-emergent AE, somnolence, occurred in 33 (63.5%) of 52 subjects. All mean vital-sign measurements and mean ECG parameters remained within normal limits after dosing and no marked changes from baseline measurements were noted. Mean values for all test results of hematology and serum chemistry panels were within the reference range at completion of the study, with no significant changes from baseline.
In these 49 healthy adult subjects, the single-dose pharmacokinetic properties of GXR 1-, 2-, and 4-mg tablets appeared to be statistically linear; that is, increases in mean C(max), AUC(0-t), and AUC(0-infinity) of guanfacine were proportional to dose, with the exception of the increase in mean C(max) between GXR 1 and 2 mg. All doses appeared to be well tolerated, with no serious AEs or withdrawal or discontinuation from study participation due to AEs reported.
胍法辛是一种α₂肾上腺素能受体激动剂，用于治疗患有注意力缺陷/多动障碍的儿童和成人。胍法辛的缓释制剂目前正在研发中。
本研究的目的是评估胍法辛缓释（GXR）片在健康成人口服后的单剂量药代动力学特性和剂量比例关系。
这是一项I期、随机、开放标签、单剂量、交叉试验，在健康成人中使用GXR 1mg、2mg和4mg片剂。在导入期（第1阶段），受试者服用一片GXR 1mg片剂，然后在4次每周一次的单独访视中随机接受GXR 2mg或4mg片剂。在给药前和96小时内定期监测生命体征、采集血样，并让受试者接受心电图（ECG）检查。在所有受试者每次服用GXR后测定Cmax、AUC(0-t)和AUC(0-∞)的药代动力学参数。分析浓度-时间数据的汇总统计量以评估剂量间的线性关系。构建方差分析模型以检验浓度-时间数据的剂量比例关系。通过分析标准血清学检查、尿液分析/药物筛查报告以及体格检查（包括身高和体重测量）、生命体征数据和ECG结果，在每次访视时评估耐受性。
该研究共纳入52名受试者，其中男性28名（53.8%），女性24名（46.2%）。受试者的平均（标准差）年龄为32.9（10.3）岁（范围18 - 54岁），平均（标准差）体重为73.4（15.7）kg（范围49.6 - 120.0 kg）。40名（76.9%）受试者为西班牙裔，7名（13.5%）为白人，5名（9.6%）为黑人。3名受试者因不遵守研究程序或使用伴随药物被研究 investigators 停用。49名受试者完成了研究。GXR 1mg、2mg和4mg时胍法辛血浆浓度的平均（标准差）值，Cmax分别为0.98（0.26）、1.57（0.51）和3.58（1.39）ng/mL；AUC(0-t)分别为29.3（8.84）、54.5（17.7）和119.1（42.3）ng/mL·h⁻¹；AUC(0-∞)分别为32.4（8.78）、58.0（18.9）和124.1（45.1）ng/mL·h⁻¹。GXR 1mg、2mg和4mg时的平均（标准差）t(1/2)值分别为17.5（3.8）、16.6（3.8）和16.7（4.90）小时。GXR 1mg与2mg、1mg与4mg以及2mg与4mg之间，Cmax、AUC(0-t)和AUC(0-∞)的几何平均比值与剂量成比例，但GXR 1mg与2mg之间Cmax增加除外。所有治疗中出现的不良事件（AE）均评估为轻度或中度，除3名受试者出现头痛和1例下背部不适经治疗缓解外，其余均无需治疗自行缓解。1名受试者报告有左肋疼痛，但由于该受试者失访，不知是否已缓解。没有受试者因AE退出研究或被研究 investigators 停用。最常见的治疗中出现的AE是嗜睡，52名受试者中有33名（63.5%）出现。给药后所有平均生命体征测量值和平均ECG参数均保持在正常范围内，与基线测量值无明显变化。研究结束时血液学和血清化学指标所有测试结果的平均值均在参考范围内，与基线无显著变化。
在这49名健康成人受试者中，GXR 1mg、2mg和4mg片剂的单剂量药代动力学特性在统计学上似乎呈线性；即胍法辛的平均Cmax、AUC(0-t)和AUC(0-∞)增加与剂量成比例，但GXR 1mg与2mg之间平均Cmax增加除外。所有剂量似乎耐受性良好，未报告有严重AE或因AE退出或停用研究参与情况。
