Ammonia Control in Children Ages 2 Months through 5 Years with Urea Cycle Disorders: Comparison of Sodium Phenylbutyrate and Glycerol Phenylbutyrate
Ammonia Control in Children Ages 2 Months through 5 Years with Urea Cycle Disorders: Comparison of Sodium Phenylbutyrate and Glycerol Phenylbutyrate
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DOI：
10.1016/j.jpeds.2012.11.084
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发表时间：
2013-06-01
影响因子：
5.1
通讯作者：
Lee, Brendan
中科院分区：
文献类型：
--
作者：
Smith, Wendy;Diaz, George A.;Lee, Brendan
目的研究苯丁酸甘油(GPB；又称HPN-100)和苯丁酸钠(NaPBA)在尿素循环障碍(UCDS)患儿中的血氨水平、药代动力学和安全性。结果15例患者(精氨酸琥珀酸裂解酶缺乏症8例，精氨酸琥珀酸合酶缺乏症3例，鸟氨酸转氨酶缺乏症3例，精氨酸氨基转移酶缺乏症1例)，年龄2个月~5岁，完成研究。每日氨暴露(24小时曲线下面积)在GPB组较低，并满足预先定义的非劣势标准(平均值比率0.79；95%可信区间0.593-1.055；P=0.03Wilcoxon；0.07t检验)。6名患者在服用GPB时发生了轻微的不良事件；没有严重的不良事件或显著的实验室变化。精氨酸琥珀酸裂解酶缺乏症患者的肝脏检查和精氨酸琥珀酸水平在GPB治疗中没有变化或有所改善。15名患者中有11名在第一天报告了35个症状；这35个症状中有23个在GPB上得到改善或解决。苯丁酸、苯乙酸和苯乙酰谷氨酰胺(PAGN)的平均全身暴露相似，服用这两种药物的最小儿童的苯乙酸暴露倾向于更高。晨间排空组尿PAGN浓度高于NaPBA组，24小时尿PAGN浓度在GPB组较NaPBA组小。结论GPB组24小时尿PAGN排出量分布更均匀，症状较少，其氨气控制效果与NaPBA组相当。
Objectives To examine ammonia levels, pharmacokinetics, and safety of glycerol phenylbutyrate (GPB; also referred to as HPN-100) and sodium phenylbutyrate (NaPBA) in young children with urea cycle disorders (UCDs).Study design This open label switch-over study enrolled patients ages 29 days to under 6 years taking NaPBA. Patients underwent 24-hour blood and urine sampling on NaPBA and again on a phenylbutyric acide-quimolar dose of GPB and completed questionnaires regarding signs and symptoms associated with NaPBA and/or their UCD.Results Fifteen patients (8 argininosuccinate lyase deficiency, 3 argininosuccinic acid synthetase deficiency, 3 ornithine transcarbamylase deficiency, 1 arginase deficiency) ages 2 months through 5 years enrolled in and completed the study. Daily ammonia exposure (24-hour area under the curve) was lower on GPB and met predefined noninferiority criteria (ratio of means 0.79; 95% CI 0.593-1.055; P = .03 Wilcoxon; 0.07 t test). Six patients experienced mild adverse events on GPB; there were no serious adverse events or significant laboratory changes. Liver tests and argininosuccinic acid levels among patients with argininosuccinate lyase deficiency were unchanged or improved on GPB. Eleven of 15 patients reported 35 symptoms on day 1; 23 of these 35 symptoms improved or resolved on GPB. Mean systemic exposure to phenylbutyric acid, phenylacetic acid, and phenylacetylglutamine (PAGN) were similar and phenylacetic acid exposure tended to be higher in the youngest children on both drugs. Urinary PAGN concentration was greater on morning voids and varied less over 24 hours on GPB versus NaPBA.Conclusions GPB results in more evenly distributed urinary output of PAGN over 24 hours were associated with fewer symptoms and offers ammonia control comparable with that observed with NaPBA in young children with UCDs.