Faessel Helene, Ravva Patanjali, Williams Kathryn
Pfizer Global Research and Development, New London, Connecticut, USA.
Clin Ther. 2009 Jan;31(1):177-89. doi: 10.1016/j.clinthera.2009.01.003.
Varenicline is approved as an aid to smoking cessation in adults aged > or =18 years.
The goal of this study was to characterize the multiple-dose pharmacokinetics, safety, and tolerability of varenicline in adolescent smokers.
This multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled healthy 12- to 16-year-old smokers (> or =3 cigarettes daily) into high-body-weight (>55 kg) and low-body-weight (< or =55 kg) groups. Subjects were randomized to receive 14 days of treatment with a high dose of varenicline, a low dose of varenicline, or placebo. The varenicline doses in the high-body-weight group were 1 mg BID and 0.5 mg BID; the varenicline doses in the low-body-weight group were 0.5 mg BID and 0.5 mg once daily. The apparent renal clearance (CL/F) and volume of distribution (V/F) of varenicline and the effect of body weight on these parameters were estimated using nonlinear mixed-effects modeling.
The high-body-weight group consisted of 35 subjects (65.7% male; 77.1% white; mean age, 15.2 years). The low-body-weight group consisted of 37 subjects (37.8% male; 48.6% white; mean age, 14.3 years). The pharmacokinetic parameters of varenicline were dose proportional over the dose range from 0.5 to 2 mg/d. The CL/F for a 70-kg adolescent was 10.4 L/h, comparable to that in a 70-kg adult. The estimated varenicline V/F was decreased in individuals of small body size, thus predicting a varenicline C(max) approximately 30% greater in low-body-weight subjects than in high-body-weight subjects. In high-body-weight subjects, steady-state varenicline exposure, as represented by the AUC(0-24), was 197.0 ng . h/mL for varenicline 1 mg BID and 95.7 ng . h/mL for varenicline 0.5 mg BID, consistent with values reported previously in adult smokers at the equivalent doses. In low-body-weight subjects, varenicline exposure was 126.3 ng . h/mL for varenicline 0.5 mg BID and 60.1 ng . h/mL for varenicline 0.5 mg once daily, values at the lower end of the range observed previously in adults at doses of 1 mg BID and 0.5 mg BID, respectively. Among high-body-weight subjects, adverse events (AEs) were reported by 57.1% of subjects in both the high- and low-dose varenicline groups and by 14.3% of subjects in the placebo group; among low-body-weight subjects, AEs were reported by 64.3%, 73.3%, and 12.5% of subjects in the high-dose varenicline, low-dose varenicline, and placebo groups, respectively. The most common AEs were nausea, headache, vomiting, and dizziness. Psychiatric AEs that were considered treatment related included abnormal dreams in 2 subjects and mild, transient anger in 1 subject. Of the AEs reported by > or =1 subject in any treatment group, > or =92% were mild in intensity. No subject discontinued the study because of an AE.
Varenicline steady-state exposure in study subjects weighing >55 kg was similar to that observed previously in adults. The body-weight effect on varenicline pharmacokinetics, which resulted in higher exposure in individuals of smaller body size (< or =55 kg), was adequately offset by administration of half the varenicline dose recommended in adults. Varenicline was generally well tolerated during the 14-day treatment period. Clinical Trials Identification Number: NCT00463918.
伐尼克兰被批准用于帮助年龄≥18岁的成年人戒烟。
本研究的目的是描述伐尼克兰在青少年吸烟者中的多剂量药代动力学、安全性和耐受性。
这项多中心、随机、双盲、安慰剂对照、平行组研究将健康的12至16岁吸烟者（每日≥3支香烟）分为高体重（>55 kg）和低体重（≤55 kg）组。受试者被随机分配接受14天的高剂量伐尼克兰、低剂量伐尼克兰或安慰剂治疗。高体重组的伐尼克兰剂量为每日2次，每次1 mg和每日2次，每次0.5 mg；低体重组的伐尼克兰剂量为每日2次，每次0.5 mg和每日1次，每次0.5 mg。使用非线性混合效应模型估计伐尼克兰的表观肾清除率（CL/F）和分布容积（V/F）以及体重对这些参数的影响。
高体重组包括35名受试者（65.7%为男性；77.1%为白人；平均年龄15.2岁）。低体重组包括37名受试者（37.8%为男性；48.6%为白人；平均年龄14.3岁）。伐尼克兰的药代动力学参数在0.5至2 mg/d的剂量范围内与剂量成比例。70 kg青少年的CL/F为10.4 L/h，与70 kg成年人相当。估计伐尼克兰的V/F在体型较小的个体中降低，因此预测低体重受试者的伐尼克兰C(max)比高体重受试者大约高30%。在高体重受试者中，以AUC(0 - 24)表示的稳态伐尼克兰暴露量，伐尼克兰每日2次，每次1 mg为197.0 ng·h/mL，伐尼克兰每日2次，每次0.5 mg为95.7 ng·h/mL，与先前报道的成年吸烟者在等效剂量下的值一致。在低体重受试者中，伐尼克兰每日2次，每次0.5 mg的暴露量为126.3 ng·h/mL，伐尼克兰每日1次，每次0.5 mg的暴露量为60.1 ng·h/mL，分别为先前在成年人中观察到的每日2次，每次1 mg和每日2次，每次0.5 mg剂量范围的下限值。在高体重受试者中，高剂量和低剂量伐尼克兰组分别有57.1%的受试者报告了不良事件（AE），安慰剂组有14.3%的受试者报告了不良事件；在低体重受试者中，高剂量伐尼克兰组有64.3%的受试者、低剂量伐尼克兰组有73.3%的受试者和安慰剂组有12.5%的受试者报告了不良事件。最常见的AE是恶心、头痛、呕吐和头晕。被认为与治疗相关的精神AE包括2名受试者出现异常梦境和1名受试者出现轻度、短暂的愤怒。在任何治疗组中，≥1名受试者报告的AE中，≥92%为轻度。没有受试者因AE而停止研究。
体重>55 kg的研究受试者中伐尼克兰的稳态暴露与先前在成年人中观察到的相似。体重对伐尼克兰药代动力学的影响导致体型较小（≤55 kg）的个体暴露量较高，通过给予成年人推荐剂量的一半伐尼克兰可充分抵消这种影响。在14天的治疗期内，伐尼克兰总体耐受性良好。临床试验识别号：NCT00463918。
