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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33 Scopus citations


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
Issue number1
StatePublished - May 2014

Bibliographical note

Funding Information:
The authors gratefully acknowledge and thank the efforts of the Study Coordinators and nursing staff who made these trials possible, including N. Schrager (Mount Sinai School of Medicine), A. Donovan, J. Crawford, Pediatric TRU Staff, K. Defouw, J. Balliet (The Medical College of Wisconsin), T. Carlson, J. Parker, S. Elsbecker (University of Minnesota), K. Simpson (Children's National Medical Center), M.B. Frohnapfel, S. Bergant, J. Haky, C. Tasi, C. Heggie (Case Western Reserve University), S. Mortenson (Maine Medical Center), M. Mullins, S. Carter, A. Tran, J. Stuff, TCH General Clinical Research Center nursing staff (Baylor College of Medicine), as well as the Clinical and Translational Science Awards/General Clinical Research Center Grants ( Baylor College of Medicine , M01RR00188 ; Case Western Reserve University , UL1RR024989 ; Clinical and Translational Science Institute at Children's National Medical Center NIH/NCRR , UL1RR31988 ; Medical College of Wisconsin , UL1RR31973 ; Mount Sinai School of Medicine , UL1RR29887 ; University of Minnesota , UL1RR33183 ; the Urea Cycle Disorders Consortium ( NIH Grant U54RR019453 ) and grants from the O'Malley Foundation and Kettering Fund which provided support. SCS Nagamani is an awardee of the National Urea Cycle Disorders Foundation Research Fellowship and the Clinical Scientist Development Award from the Doris Duke Charitable Foundation.


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


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