新型氨清除剂与苯丁酸钠在尿素循环障碍患者中的 2 期比较：安全性、药代动力学和氨控制。
Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: safety, pharmacokinetics and ammonia control.
机构信息
Baylor College of Medicine, Houston, TX, USA.
出版信息
Mol Genet Metab. 2010 Jul;100(3):221-8. doi: 10.1016/j.ymgme.2010.03.014. Epub 2010 Mar 23.
UNLABELLED
Glycerol phenylbutyrate (glyceryl tri (4-phenylbutyrate)) (GPB) is being studied as an alternative to sodium phenylbutyrate (NaPBA) for the treatment of urea cycle disorders (UCDs). This phase 2 study explored the hypothesis that GPB offers similar safety and ammonia control as NaPBA, which is currently approved as adjunctive therapy in the chronic management of UCDs, and examined correlates of 24-h blood ammonia.
METHODS
An open-label, fixed sequence switch-over study was conducted in adult UCD patients taking maintenance NaPBA. Blood ammonia and blood and urine metabolites were compared after 7 days (steady state) of TID dosing on either drug, both dosed to deliver the same amount of phenylbutyric acid (PBA).
RESULTS
Ten subjects completed the study. Adverse events were comparable for the two drugs; 2 subjects experienced hyperammonemic events on NaPBA while none occurred on GPB. Ammonia values on GPB were approximately 30% lower than on NaPBA (time-normalized AUC=26.2 vs. 38.4 micromol/L; Cmax=56.3 vs. 79.1 micromol/L; not statistically significant), and GPB achieved non-inferiority to NaPBA with respect to ammonia (time-normalized AUC) by post hoc analysis. Systemic exposure (AUC(0-24)) to PBA on GPB was 27% lower than on NaPBA (540 vs. 739 microgh/mL), whereas exposure to phenylacetic acid (PAA) (575 vs. 596 microg h/mL) and phenylacetylglutamine (PAGN) (1098 vs. 1133 microg h/mL) were similar. Urinary PAGN excretion accounted for approximately 54% of PBA administered for both NaPBA and GPB; other metabolites accounted for <1%. Intact GPB was generally undetectable in blood and urine. Blood ammonia correlated strongly and inversely with urinary PAGN (r=-0.82; p<0.0001) but weakly or not at all with blood metabolite levels.
CONCLUSIONS
Safety and ammonia control with GPB appear at least equal to NaPBA. Urinary PAGN, which is stoichiometrically related to nitrogen scavenging, may be a useful biomarker for both dose selection and adjustment for optimal control of venous ammonia.
目的
甘油苯丁酸（甘油三（4-苯丁酸酯））（GPB）作为苯丁酸钠（NaPBA）的替代品，用于治疗尿素循环障碍（UCD）。这项 2 期研究旨在验证 GPB 在安全性和氨控制方面与目前批准用于 UCD 慢性管理的辅助治疗的 NaPBA 相似，并探讨 24 小时血氨的相关因素。
方法
对接受维持性 NaPBA 治疗的成年 UCD 患者进行开放标签、固定序列转换研究。在两种药物（均以提供相同量的苯丁酸（PBA）的 TID 剂量给药）给药 7 天后（达到稳态），比较血氨以及血和尿代谢物。
结果
10 名受试者完成了研究。两种药物的不良事件相似；2 名患者在 NaPBA 时发生高氨血症事件，而 GPB 时则没有。GPB 的氨值比 NaPBA 低约 30%（时间归一化 AUC=26.2 与 38.4 μmol/L；Cmax=56.3 与 79.1 μmol/L；无统计学意义），并且通过事后分析，GPB 在氨（时间归一化 AUC）方面达到了与 NaPBA 的非劣效性。GPB 对 PBA 的全身暴露（AUC（0-24））比 NaPBA 低 27%（540 与 739 μg h/mL），而对苯乙酸（PAA）（575 与 596 μg h/mL）和苯乙酰谷氨酰胺（PAGN）（1098 与 1133 μg h/mL）的暴露相似。尿 PAGN 排泄占给予 NaPBA 和 GPB 的 PBA 的约 54%；其他代谢物占比<1%。血和尿中通常无法检测到完整的 GPB。血氨与尿 PAGN 呈强负相关（r=-0.82；p<0.0001），但与血代谢物水平的相关性较弱或没有。
结论
GPB 的安全性和氨控制似乎至少与 NaPBA 相当。尿 PAGN 与氮清除量成化学计量关系，可能是用于选择剂量和调整静脉氨最佳控制的有用生物标志物。
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