Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: Safety, pharmacokinetics and ammonia control

Brendan Lee, William Rhead, George A. Diaz, Bruce F. Scharschmidt, Asad Mian, Oleg Shchelochkov, J. F. Marier, Martin Beliveau, Joseph Mauney, Klara Dickinson, Antonia Martinez, Sharron Gargosky, Masoud Mokhtarani, Susan A. Berry

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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 ∼30% lower than on NaPBA (time-normalized AUC = 26.2 vs. 38.4 μmol/L; Cmax = 56.3 vs. 79.1 μmol/L; not statistically significant), and GPB achieved non-inferiority to NaPBA with respect to ammonia (time-normalized AUC) by post hoc analysis. Systemic exposure (AUC0-24) to PBA on GPB was 27% lower than on NaPBA (540 vs. 739 μg h/mL), whereas exposure to phenylacetic acid (PAA) (575 vs. 596 μg h/mL) and phenylacetylglutamine (PAGN) (1098 vs. 1133 μg h/mL) were similar. Urinary PAGN excretion accounted for ∼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.

Original languageEnglish (US)
Pages (from-to)221-228
Number of pages8
JournalMolecular Genetics and Metabolism
Issue number3
StatePublished - Jul 2010

Bibliographical note

Funding Information:
The authors acknowledge the clinical research staffs at Baylor College of Medicine (Mary Mullins, Susan Carter, and Alyssa Tran), the Medical College of Wisconsin (Patricia Chico, MA), the Mt Sinai School of Medicine (Javier Delgado, Christina Guzman) and the University of Minnesota (Judith Parker, Lori Carlson, and Melissa Spence). The work was supported in part by the Baylor College of Medicine General Clinical Research Center (RR00188), Baylor Mental Retardation and Developmental Disabilities Research Center (HD024064), the Baylor Child Health Research Center (HD041648), the Mt. Sinai School of Medicine General Clinical Research Center (RR000071), the University of Minnesota General Clinical Research Center (RR00400), the Urea Cycle Disorders Consortium (NIH Grant RR019453 and the O’Malley Foundation), and the NIH (Dr. Lee [DK54450]). Dr. Shchelochkov was supported by a Urea Cycle Disorders Rare Disease Clinical Research Consortium O’Malley Foundation Fellowship and a National Urea Cycle Disorders Foundation Fellowship.


  • Ammonia
  • Clinical trial
  • Phenylacetylglutamine
  • Phenylbutyrate
  • Urea cycle disorders


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