title: Urinary phenylacetylglutamine as dosing biomarker for patients with urea cycle disorders.
abstract: We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD).
  
  
  METHODS
  These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine.
  
  
  RESULTS
  Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p<0.001), followed by plasma phenylacetylglutamine AUC(24-hour), plasma phenylacetic acid AUC(24-hour) and phenylbutyric acid AUC(24-hour). Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control.
  
  
  CONCLUSIONS
  The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring.
authors.affiliation: Hyperion Therapeutics, 601 Gateway Blvd, Suite 200, South San Francisco, CA 94080, USA. Masoud.mokhtarani@hyperiontx.com
authors.forename: M
authors.initials: M
authors.lastname: Mokhtarani
authors.forename: G A
authors.initials: GA
authors.lastname: Diaz
authors.forename: W
authors.initials: W
authors.lastname: Rhead
authors.forename: U
authors.initials: U
authors.lastname: Lichter-Konecki
authors.forename: J
authors.initials: J
authors.lastname: Bartley
authors.forename: A
authors.initials: A
authors.lastname: Feigenbaum
authors.forename: N
authors.initials: N
authors.lastname: Longo
authors.forename: W
authors.initials: W
authors.lastname: Berquist
authors.forename: S A
authors.initials: SA
authors.lastname: Berry
authors.forename: R
authors.initials: R
authors.lastname: Gallagher
authors.forename: D
authors.initials: D
authors.lastname: Bartholomew
authors.forename: C O
authors.initials: CO
authors.lastname: Harding
authors.forename: M S
authors.initials: MS
authors.lastname: Korson
authors.forename: S E
authors.initials: SE
authors.lastname: McCandless
authors.forename: W
authors.initials: W
authors.lastname: Smith
authors.forename: J
authors.initials: J
authors.lastname: Vockley
authors.forename: S
authors.initials: S
authors.lastname: Bart
authors.forename: D
authors.initials: D
authors.lastname: Kronn
authors.forename: R
authors.initials: R
authors.lastname: Zori
authors.forename: S
authors.initials: S
authors.lastname: Cederbaum
authors.forename: N
authors.initials: N
authors.lastname: Dorrani
authors.forename: J L
authors.initials: JL
authors.lastname: Merritt
authors.forename: Sandesh
authors.initials: S
authors.lastname: Sreenath-Nagamani
authors.forename: M
authors.initials: M
authors.lastname: Summar
authors.forename: C
authors.initials: C
authors.lastname: Lemons
authors.forename: K
authors.initials: K
authors.lastname: Dickinson
authors.forename: D F
authors.initials: DF
authors.lastname: Coakley
authors.forename: T L
authors.initials: TL
authors.lastname: Moors
authors.forename: B
authors.initials: B
authors.lastname: Lee
authors.forename: B F
authors.initials: BF
authors.lastname: Scharschmidt
mesh_terms: D000293:Adolescent; D000328:Adult; D000641:Ammonia / Q000097:blood / Q000652:urine*; D054316:Biomarkers, Pharmacological / Q000097:blood / Q000652:urine; D002648:Child; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D005260:Female; D005973:Glutamine / Q000031:analogs & derivatives* / Q000097:blood / Q000652:urine; D005990:Glycerol / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D006801:Humans; D008297:Male; D010648:Phenylacetates / Q000097:blood / Q000652:urine*; D010654:Phenylbutyrates / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine*; D056806:Urea Cycle Disorders, Inborn / Q000097:blood / Q000188:drug therapy* / Q000652:urine*
chemical_list: D054316:Biomarkers, Pharmacological; D010648:Phenylacetates; D010654:Phenylbutyrates; D005973:Glutamine; D000641:Ammonia; C003089:phenylacetylglutamine; C025136:phenylacetic acid; D005990:Glycerol; C570223:glycerol phenylbutyrate