title: Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: safety, pharmacokinetics and ammonia control.
abstract: 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 approximately 30% lower than on NaPBA (time-normalized AUC=26.2 vs. 38.4 micromol/L; Cmax=56.3 vs. 79.1 micromol/L; not statistically significant), and GPB achieved non-inferiority to NaPBA with respect to ammonia (time-normalized AUC) by post hoc analysis. Systemic exposure (AUC(0-24)) to PBA on GPB was 27% lower than on NaPBA (540 vs. 739 microgh/mL), whereas exposure to phenylacetic acid (PAA) (575 vs. 596 microg h/mL) and phenylacetylglutamine (PAGN) (1098 vs. 1133 microg h/mL) were similar. Urinary PAGN excretion accounted for approximately 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.
authors.affiliation: Baylor College of Medicine, Houston, TX, USA. blee@bcm.tmc.edu
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
authors.forename: William
authors.initials: W
authors.lastname: Rhead
authors.forename: George A
authors.initials: GA
authors.lastname: Diaz
authors.forename: Bruce F
authors.initials: BF
authors.lastname: Scharschmidt
authors.forename: Asad
authors.initials: A
authors.lastname: Mian
authors.forename: Oleg
authors.initials: O
authors.lastname: Shchelochkov
authors.forename: J F
authors.initials: JF
authors.lastname: Marier
authors.forename: Martin
authors.initials: M
authors.lastname: Beliveau
authors.forename: Joseph
authors.initials: J
authors.lastname: Mauney
authors.forename: Klara
authors.initials: K
authors.lastname: Dickinson
authors.forename: Antonia
authors.initials: A
authors.lastname: Martinez
authors.forename: Sharron
authors.initials: S
authors.lastname: Gargosky
authors.forename: Masoud
authors.initials: M
authors.lastname: Mokhtarani
authors.forename: Susan A
authors.initials: SA
authors.lastname: Berry
mesh_terms: D000328:Adult; D000368:Aged; D000641:Ammonia / Q000097:blood*; D018592:Cross-Over Studies; D005260:Female; D005973:Glutamine / Q000031:analogs & derivatives / Q000097:blood; D005990:Glycerol / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D010648:Phenylacetates / Q000097:blood; D010654:Phenylbutyrates / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D056806:Urea Cycle Disorders, Inborn / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D010648:Phenylacetates; D010654:Phenylbutyrates; D005973:Glutamine; D000641:Ammonia; C075773:4-phenylbutyric acid; C003089:phenylacetylglutamine; C025136:phenylacetic acid; D005990:Glycerol
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