Children's National Medical Center, Washington, DC, 20010, USA.
Mol Genet Metab. 2011 Aug;103(4):323-9. doi: 10.1016/j.ymgme.2011.04.013. Epub 2011 May 5.
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 24h 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.
在一项对苯丁酸钠（NaPBA）和甘油苯丁酸钠（GPB 或 HPN-100）的 2 期比较中，研究了 24 小时氨谱和药物作用的相关性，这是一种正在开发用于尿素循环障碍（UCD）的研究药物。
方案 HPN-100-005 涉及从规定的 NaPBA 剂量到 PBA 等摩尔 GPB 剂量的开放标签固定序列转换，并进行饮食控制。在接受 NaPBA 或 GPB 治疗 7 天后，对患者进行 24 小时血液采样，以检测氨和药物代谢物水平，并测量 24 小时尿苯乙酰谷氨酰胺（PAGN）。监测不良事件（AE）、安全性实验室和三重复心电图。
11 名受试者（9 名 OTC、1 名 ASS、1 名 ASL）入组并完成了从 NaPBA（平均剂量=12.4 g/d 或 322mg/kg/d；范围=198-476mg/kg/d）到 GPB（平均剂量=10.8 mL 或 0.284 mL/kg/d 或 313mg/kg/d；范围=192-449mg/kg/d）的转换。在接受 NaPBA 的 2 名受试者和接受 GPB 的 4 名受试者中报告了可能与药物相关的 AE。所有 AE 均为轻度，除了 1 名中度 AE 为接受 GPB 治疗的呕吐，与并发疾病有关。未观察到临床显著的实验室或心电图变化。空腹后氨最低，下午至傍晚餐前达到峰值，24 小时内变化很大，偶尔超过 100μmol/L 而无症状。与 NaPBA 相比，GPB 时的氨值降低了约 25%（对于 ITT，p≥0.1；对于方案人群，p<0.05）。在 ITT 人群中，GPB 与 NaPBA 之间氨值差异的上限 95%置信区间（95%CI 0.575，1.061；p=0.102）小于预设的非劣效性边界 1.25，在预设的方案人群中小于 1.0（95%CI 0.516，0.958；p<0.05）。与接受 NaPBA 治疗相比，接受 GPB 治疗时，血浆苯乙酸和 PAGN 暴露无统计学显著差异，口服给予的 PBA 排泄为 PAGN 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 在控制氨方面至少与 NaPBA 等效，在儿科 UCD 患者中具有潜在的应用价值，U-PAGN 是一种用于剂量选择和监测的临床有用的生物标志物。
