title: 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).
  
  
  METHODS
  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.
authors.affiliation: University of Minnesota, Minneapolis, MN, USA. Electronic address: berry002@umn.edu.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Berry
authors.affiliation: Children's National Medical Center, Washington, DC, USA.
authors.forename: Uta
authors.initials: U
authors.lastname: Lichter-Konecki
authors.affiliation: Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, Department of Pediatrics, New York, NY, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Diaz
authors.affiliation: Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Shawn E
authors.initials: SE
authors.lastname: McCandless
authors.affiliation: The Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: William
authors.initials: W
authors.lastname: Rhead
authors.affiliation: Maine Medical Center, Portland, ME, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Smith
authors.affiliation: National Urea Cycle Disorders Foundation, 75 S. Grand Ave., Pasadena, CA 91105, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lemons
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: Sandesh C S
authors.initials: SC
authors.lastname: Nagamani
authors.affiliation: Hyperion Therapeutics, South San Francisco, CA, USA.
authors.forename: Dion F
authors.initials: DF
authors.lastname: Coakley
authors.affiliation: Hyperion Therapeutics, South San Francisco, CA, USA.
authors.forename: Masoud
authors.initials: M
authors.lastname: Mokhtarani
authors.affiliation: Hyperion Therapeutics, South San Francisco, CA, USA.
authors.forename: Bruce F
authors.initials: BF
authors.lastname: Scharschmidt
authors.affiliation: Baylor College of Medicine, Houston, TX, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000641:Ammonia / Q000097:blood; D002648:Child; D002675:Child, Preschool; D018592:Cross-Over Studies; D005260:Female; D005973:Glutamine / Q000652:urine; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010654:Phenylbutyrates / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D056806:Urea Cycle Disorders, Inborn / Q000178:diet therapy / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D010654:Phenylbutyrates; D005973:Glutamine; D000641:Ammonia
keywords: Ammonia; Children; Glutamine; Glycerol phenylbutyrate; Urea cycle disorders