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Glycerol phenylbutyrate treatment in children with urea cycle disorders: pooled analysis of short and long-term ammonia control and outcomes.

Abstract：

OBJECTIVE:To evaluate glycerol phenylbutyrate (GPB) in the treatment of pediatric patients with urea cycle disorders (UCDs). STUDY DESIGN:UCD patients (n=26) ages 2months through 17years were treated with GPB and sodium phenylbutyrate (NaPBA) in two short-term, open-label crossover studies, which compared 24-hour ammonia exposure (AUC0-24) and glutamine levels during equivalent steady-state dosing of GPB and sodium phenylbutyrate (NaPBA). These 26 patients plus an additional 23 patients also received GPB in one of three 12-month, open label extension studies, which assessed long-term ammonia control, hyperammonemic (HA) crises, amino acid levels, and patient growth. RESULTS:Mean ammonia exposure on GPB was non-inferior to NaPBA in each of the individual crossover studies. In the pooled analyses, it was significantly lower on GPB vs. NaPBA (mean [SD] AUC0-24: 627 [302] vs. 872 [516] μmol/L; p=0.008) with significantly fewer abnormal values (15% on GPB vs. 35% on NaPBA; p=0.02). Mean ammonia levels remained within the normal range during 12months of GPB dosing and, when compared with the 12months preceding enrollment, a smaller percentage of patients (24.5% vs. 42.9%) experienced fewer (17 vs. 38) HA crises. Glutamine levels tended to be lower with GPB than with NaPBA during short-term dosing (mean [SD]: 660.8 [164.4] vs. 710.0 [158.7] μmol/L; p=0.114) and mean glutamine and branched chain amino acid levels, as well as other essential amino acids, remained within the normal range during 12months of GPB dosing. Mean height and weight Z-scores were within normal range at baseline and did not change significantly during 12months of GPB treatment. CONCLUSIONS:Dosing with GPB was associated with 24-hour ammonia exposure that was non-inferior to that during dosing with NaPBA in individual studies and significantly lower in the pooled analysis. Long-term GPB dosing was associated with normal levels of glutamine and essential amino acids, including branched chain amino acids, age-appropriate growth and fewer HA crises as compared with the 12month period preceding enrollment.

journal_name

Mol Genet Metab

journal_title

Molecular genetics and metabolism

authors

Berry SA,Lichter-Konecki U,Diaz GA,McCandless SE,Rhead W,Smith W,Lemons C,Nagamani SC,Coakley DF,Mokhtarani M,Scharschmidt BF,Lee B

doi

10.1016/j.ymgme.2014.02.007

subject

Has Abstract

pub_date

2014-05-01 00:00:00

pages

17-24

issue

eissn

1096-7192

issn

1096-7206

pii

S1096-7192(14)00071-7

journal_volume

112

pub_type

临床试验,杂志文章

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Glycerol phenylbutyrate treatment in children with urea cycle disorders: pooled analysis of short and long-term ammonia control and outcomes.