Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate.
Ammonia control in children with urea cycle disorders (UCDs); phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate.
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DOI：
10.1016/j.ymgme.2011.04.013
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发表时间：
2011-08
影响因子：
3.8
通讯作者：
Rhead W
中科院分区：
文献类型：
--
作者：
Lichter-Konecki U;Diaz GA;Merritt JL 2nd;Feigenbaum A;Jomphe C;Marier JF;Beliveau M;Mauney J;Dickinson K;Martinez A;Mokhtarani M;Scharschmidt B;Rhead W
在苯丁酸钠（NaPBA）和苯丁酸甘油酯（GPB或HPN-100）（一种正在开发用于尿素循环障碍（UCD）的研究药物）的II期比较中，检查了24小时氨曲线和药物效应的相关性。方案HPN-100-005涉及从处方NaPBA剂量转换为PBA-等摩尔GPB剂量的开放标签固定序列，并控制饮食。在NaPBA或GPB治疗7天后，受试者接受了24小时血液采样，用于氨和药物代谢物水平以及24小时尿苯乙酰谷氨酰胺（PAGN）测量。监测不良事件（AE）、安全性实验室检查和三次心电图。11例受试者（9例OTC、1例ASS、1例ASL）入组并完成了从NaPBA（平均剂量=12.4 g/d或322 mg/kg/d;范围=198-476 mg/kg/d）转换为GPB（平均剂量=10.8 mL或0.284 mL/kg/d或313 mg/kg/d;范围= 192-449 mg/kg/d）。NaPBA组2例受试者和GPB组4例受试者报告了可能相关的AE。除1起与并发疾病相关的GPB呕吐中度AE外，所有AE均为轻度。未观察到具有临床意义的实验室或ECG变化。夜间禁食后血氨最低，餐后下午至傍晚达到峰值，24 h内变化较大，偶尔值>100 μmol/L，无症状。GPB组的氨值比NaPBA组低约25%（ITT组p ≥ 0.1，符合方案人群p<0.05）。ITT人群中氨对GPB与NaPBA之间差异的95%置信区间上限（95% CI 0.575，1.061; p = 0.102）小于预定义的非劣效性界值1.25，并且小于预定义的符合方案人群中的1.0（95% CI 0.516，0.958; p<0.05）。在GPB与NaPBA给药期间，未观察到血浆苯乙酸和PAGN暴露量的统计学显著差异，并且经口给药的PBA以PAGN形式排泄的百分比（GPB为66%，NaPBA为69%）非常相似。GPB和NaPBA剂量与尿PAGN相关性最好。这些发现表明，GPB在氨控制方面至少与NaPBA相当，在儿科UCD患者中具有潜在的实用性，并且U-PAGN是剂量选择和监测的临床有用的生物标志物。
Twenty four hour ammonia profiles and correlates of drug effect were examined in a phase 2 comparison of sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB or HPN-100), an investigational drug being developed for urea cycle disorders (UCDs). Protocol HPN-100-005 involved open label fixed-sequence switch-over from the prescribed NaPBA dose to a PBA-equimolar GPB dose with controlled diet. After 7 days on NaPBA or GPB, subjects underwent 24-hour blood sampling for ammonia and drug metabolite levels as well as measurement of 24-hour urinary phenyacetylglutamine (PAGN). Adverse events (AEs), safety labs and triplicate ECGs were monitored. Eleven subjects (9 OTC, 1 ASS, 1 ASL) enrolled and completed the switch-over from NaPBA (mean dose=12.4 g/d or 322 mg/kg/d; range=198–476 mg/kg/d) to GPB (mean dose=10.8 mL or 0.284 mL/kg/d or 313 mg/kg/d; range = 192–449 mg/kg/d). Possibly-related AEs were reported in 2 subjects on NaPBA and 4 subjects on GPB. All were mild, except for one moderate AE of vomiting on GPB related to an intercurrent illness. No clinically significant laboratory or ECG changes were observed. Ammonia was lowest after overnight fast, peaked postprandially in the afternoon to early evening and varied widely over 24 h with occasional values >100 μmol/L without symptoms. Ammonia values were ~25% lower on GPB vs. NaPBA (p ≥ 0.1 for ITT and p<0.05 for per protocol population). The upper 95% confidence interval for the difference between ammonia on GPB vs. NaPBA in the ITT population (95% CI 0.575, 1.061; p = 0.102) was less than the predefined non-inferiority margin of 1.25 and less than 1.0 in the pre-defined per-protocol population (95% CI 0.516, 0.958; p<0.05). No statistically significant differences were observed in plasma phenylacetic acid and PAGN exposure during dosing with GPB vs. NaPBA, and the percentage of orally administered PBA excreted as PAGN (66% for GPB vs. 69% for NaPBA) was very similar. GPB and NaPBA dose correlated best with urinary-PAGN. These findings suggest that GPB is at least equivalent to NaPBA in terms of ammonia control, has potential utility in pediatric UCD patients and that U-PAGN is a clinically useful biomarker for dose selection and monitoring.