PDF(Pubmed)
Abstract：
Achondroplasia (ACH) is a common skeletal dysplasia characterized by a disproportionately short stature. We found that meclizine, which is an over-the-counter drug for motion sickness, inhibited the fibroblast growth factor receptor 3 (FGFR3) gene using a drug repositioning strategy, and meclizine 1 and 2 mg/kg/day promoted bone growth in a mouse model of ACH. A previous phase 1a clinical trial for children with ACH demonstrated that a single dose of meclizine 25 and 50 mg was safe and that the simulated plasma concentration achieved steady state approximately 10 days after the first dose. The current study aimed to evaluate the safety and pharmacokinetics (PK) of meclizine in children with ACH after a 14-day-repeated dose of meclizine. Twelve patients with ACH aged 5-10 years were enrolled. Meclizine 12.5 (cohort 1) and 25 mg/day (cohort 2) were administered after meals for 14 days, and adverse events (AEs) and PK were evaluated. No patient experienced serious AEs in either group. The average (95% confidential interval [CI]) maximum drug concentration (Cmax), peak drug concentration (Tmax), area under the curve (AUC) from 0 to 24 h, and terminal elimination half-life (t1/2) after a 14-day-repeated administration of meclizine (12.5 mg) were 167 (83-250) ng/mL, 3.7 (3.1-4.2) h, 1170 (765-1570) ng·h/mL, and 7.4 (6.7-8.0) h, respectively. The AUC0-6h after the final administration was 1.5 times that after the initial dose. Cmax and AUC were higher in cohort 2 than in cohort 1 in a dose-dependent manner. Regarding the regimen of meclizine 12.5 and 25 mg in patients < 20 kg and ≥ 20 kg, respectively, the average (95% CI) AUC0-24h was 1270 (1100-1440) ng·h/mL. Compartment models demonstrated that the plasma concentration of meclizine achieved at a steady state after the 14th administration. Long-term administration of meclizine 12.5 or 25 mg/day is recommended for phase 2 clinical trials in children with ACH.
摘要：
软骨发育不良（ACH）是一种常见的骨骼发育不良，其特征是身材矮小。我们发现meclizine,这是一种治疗晕车的非处方药，使用药物重新定位策略抑制成纤维细胞生长因子受体3（FGFR3）基因，和meclizine1和2mg/kg/天促进ACH小鼠模型的骨生长。先前针对ACH儿童的1a期临床试验表明，单剂量的meclizine25和50mg是安全的，并且模拟的血浆浓度在第一次给药后约10天达到稳态。本研究旨在评估14天重复剂量的美克利嗪在ACH儿童中的安全性和药代动力学（PK）。纳入12例年龄5-10岁的ACH患者。Meclizine12.5（队列1）和25mg/天（队列2）在餐后给药14天，和不良事件（AE）和PK进行评估。两组均无患者出现严重AE。平均（95%保密区间[CI]）最大药物浓度（Cmax），峰值药物浓度（Tmax），从0到24小时的曲线下面积（AUC），和终末消除半衰期（t1/2）14天重复给药后的美克利嗪（12.5毫克）为167（83-250）ng/mL，3.7(3.1-4.2)h,1170（765-1570）ng·h/mL，和7.4(6.7-8.0)小时，分别。最终给药后的AUC0-6h是初始剂量后的1.5倍。Cmax和AUC在队列2中以剂量依赖性方式高于队列1。关于在<20kg和≥20kg的患者中使用meclizine12.5和25mg的方案，分别,平均(95%CI)AUC0-24h为1270(1100-1440)ng·h/mL。隔室模型表明，第14次给药后，美克利嗪的血浆浓度达到稳态。对于ACH儿童的2期临床试验，建议长期服用meclizine12.5或25mg/天。
