Webb Nicholas J A, Wells Thomas, Tsai Max, Zhao Zhen, Juhasz Attila, Dudkowski Caroline
Department of Paediatric Nephrology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, M13 9WL, UK.
Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
Eur J Clin Pharmacol. 2016 Apr;72(4):447-57. doi: 10.1007/s00228-015-1987-8. Epub 2016 Jan 4.
This open-label, multicenter, single-dose study characterized the pharmacokinetics and short-term safety of azilsartan medoxomil (AZL-M) in hypertensive pediatric subjects (12-16 years [cohort 1a; n = 9]; 6-11 years [cohort 2; n = 8]; 4-5 years [cohort 3; n = 3]).
Model-based simulations were performed to guide dosing, especially in 1-5-year olds, who were difficult to enroll. AZL-M was dosed according to body weight (20-60-mg tablet, cohorts 1a and 2; 0.66 mg/kg granule suspension, cohort 3). In cohort 1, gender-matched healthy adults (cohort 1b; n = 9) received AZL-M 80 mg.
Exposure to AZL (active moiety of AZL-M), measured by dose-/body weight-normalized C max and AUC0-∞, was ∼15-30 % lower in pediatric subjects versus adults. In simulations, exposure with 0.66 mg/kg AZL-M in pediatric subjects weighing 8-25 kg approximated to AZL-M 40 mg (typical starting dose) in adults. The simulations suggest that 25-50-kg subjects require half the adult dose (10-40 mg), whereas 50-100-kg subjects can use the same dosing as adults. Adverse events were mild in intensity, apart from one moderate event (migraine).
This dosing strategy should be safe in pediatric patients, as AZL exposure would not exceed that seen in adults with the highest approved AZL-M dose (80 mg).
本开放标签、多中心、单剂量研究旨在表征阿齐沙坦美洛昔酯（AZL-M）在高血压儿科受试者（12至16岁[队列1a；n = 9]；6至11岁[队列2；n = 8]；4至5岁[队列3；n = 3]）中的药代动力学和短期安全性。
进行基于模型的模拟以指导给药，尤其是在难以招募受试者的1至5岁儿童中。AZL-M根据体重给药（20至60毫克片剂，队列1a和2；0.66毫克/千克颗粒混悬液，队列3）。在队列1中，性别匹配的健康成年人（队列1b；n = 9）接受80毫克AZL-M。
通过剂量/体重标准化的Cmax和AUC0-∞测量，儿科受试者中阿齐沙坦（AZL-M的活性部分）的暴露量比成年人低约15%至30%。在模拟中，体重8至25千克的儿科受试者使用0.66毫克/千克AZL-M的暴露量近似于成年人使用40毫克AZL-M（典型起始剂量）的暴露量。模拟结果表明，体重25至50千克的受试者需要成人剂量的一半（10至40毫克），而体重50至100千克的受试者可以使用与成年人相同的剂量。除了1例中度事件（偏头痛）外，不良事件的强度均为轻度。
这种给药策略在儿科患者中应是安全的，因为AZL的暴露量不会超过批准的最高AZL-M剂量（80毫克）的成年人。
