Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia
Pharmacokinetics and safety after once and twice a day doses of meclizine hydrochloride administered to children with achondroplasia
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DOI：
10.1371/journal.pone.0229639
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发表时间：
2020-04-13
期刊：
影响因子：
3.7
通讯作者：
Ishiguro, Naoki
中科院分区：
文献类型：
--
作者：
Kitoh, Hiroshi;Matsushita, Masaki;Ishiguro, Naoki
软骨发育不全（achdroplasia， ACH）是由成纤维细胞生长因子受体3 （FGFR3）基因激活突变引起的最常见的短肢骨骼发育不良。我们发现，在ACH小鼠模型中，盐酸美氯嗪抑制各种软骨细胞中的FGFR3信号传导，促进纵向骨生长。美氯嗪已经安全使用了50多年，但它缺乏重复给药的安全性数据和给药儿童时的药代动力学（PK）。我们进行了一项i期研究，以评估口服美利嗪给ACH儿童的PK和安全性。招募12名年龄在5岁至11岁以下的ACH儿童，前6名受试者在禁食状态下每天给予1次美唑嗪，随后6名受试者在进食状态下每天给予2次美唑嗪。美唑嗪在ACH患儿中耐受性良好，无严重不良事件。空腹24h的平均C-max、T-max、AUC（0-24h）、t1/2分别为130 ng/mL、1.7 h、761 ng.h/mL和8.5 h。反复给药14天的模拟实验表明，无论是一天一次给药还是一天两次给药，在第一次给药后10天左右血药浓度明显达到稳定状态。禁食和饲喂条件下的AUC（0-10h）分别为504 ng.h/mL和813 ng.h/mL，表明甲氧苄嗪的暴露量随着日粮的增加而增加。虽然证实ACH儿童的药物暴露比成人高，但单次给药美唑嗪似乎耐受性良好。
Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We identified that meclizine hydrochloride inhibited FGFR3 signaling in various chondrocytic cells and promoted longitudinal bone growth in mouse model of ACH. Meclizine has safely been used for more than 50 years, but it lacks the safety data for repeated administration and pharmacokinetics (PK) when administered to children. We performed a phase Ia study to evaluate the PK and safety of meclizine administered orally to ACH children. Twelve ACH children aged from 5 to younger than 11 years were recruited, and the first 6 subjects received once a day of meclizine in the fasted condition, subsequent 6 subjects received twice a day of meclizine in the fed condition. Meclizine was well tolerated in ACH children with no serious adverse events. The mean C-max, T-max, AUC(0-24h), t1/2 during 24 hours in the fasted condition were 130 ng/mL, 1.7 hours, 761 ng.h/mL, and 8.5 hours respectively. The simulation of repeated administration of meclizine for 14 days demonstrated that plasma concentration apparently reached steady state around 10 days after the first dose both at once a day and twice a day administration. The AUC(0-10h) of the fasting and fed condition were 504 ng.h/mL and 813 ng.h/mL, respectively, indicating exposure of meclizine increased with the diet. Although higher drug exposure was confirmed in ACH children compared to adults, a single administration of meclizine seemed to be well tolerated.