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

Susan A. Berry, Uta Lichter-Konecki, George A. Diaz, Shawn E. McCandless, William Rhead, Wendy Smith, Cynthia LeMons, Sandesh C.S. Nagamani, Dion F. Coakley, Masoud Mokhtarani, Bruce F. Scharschmidt, Brendan Lee

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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 12. month period preceding enrollment.

Original languageEnglish (US)
Pages (from-to)17-24
Number of pages8
JournalMolecular Genetics and Metabolism
Volume112
Issue number1
DOIs
StatePublished - May 2014

Keywords

  • Ammonia
  • Children
  • Glutamine
  • Glycerol phenylbutyrate
  • Urea cycle disorders

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    Berry, S. A., Lichter-Konecki, U., Diaz, G. A., McCandless, S. E., Rhead, W., Smith, W., LeMons, C., Nagamani, S. C. S., Coakley, D. F., Mokhtarani, M., Scharschmidt, B. F., & Lee, B. (2014). Glycerol phenylbutyrate treatment in children with urea cycle disorders: Pooled analysis of short and long-term ammonia control and outcomes. Molecular Genetics and Metabolism, 112(1), 17-24. https://doi.org/10.1016/j.ymgme.2014.02.007