title: Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio.
abstract: BACKGROUND
  Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥ 500 μg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels.
  
  
  METHODS
  The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of ≥ 2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values.
  
  
  RESULTS
  Only 0.2% (11) of 4683 samples exceeded 500 μg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio>2.5 (both in μg/mL) in a random blood draw identified patients at risk for PAA levels>500 μg/ml.
  
  
  CONCLUSIONS
  The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.
authors.affiliation: Hyperion Therapeutics, 601 Gateway Blvd., Suite 200, South San Francisco, CA 94080, USA. Electronic address: Masoud.mokhtarani@hyperiontx.com.
authors.forename: M
authors.initials: M
authors.lastname: Mokhtarani
authors.forename: G A
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authors.lastname: Diaz
authors.forename: W
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authors.lastname: Rhead
authors.forename: S A
authors.initials: SA
authors.lastname: Berry
authors.forename: U
authors.initials: U
authors.lastname: Lichter-Konecki
authors.forename: A
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authors.lastname: Feigenbaum
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authors.lastname: Schulze
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authors.initials: N
authors.lastname: Longo
authors.forename: J
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authors.lastname: Bartley
authors.forename: W
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authors.lastname: Berquist
authors.forename: R
authors.initials: R
authors.lastname: Gallagher
authors.forename: W
authors.initials: W
authors.lastname: Smith
authors.forename: S E
authors.initials: SE
authors.lastname: McCandless
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authors.initials: C
authors.lastname: Harding
authors.forename: D C
authors.initials: DC
authors.lastname: Rockey
authors.forename: J M
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authors.lastname: Vierling
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authors.initials: P
authors.lastname: Mantry
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authors.lastname: Ghabril
authors.forename: R S
authors.initials: RS
authors.lastname: Brown
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authors.lastname: Moors
authors.forename: C
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authors.lastname: Norris
authors.forename: D
authors.initials: D
authors.lastname: Coakley
authors.forename: D A
authors.initials: DA
authors.lastname: Milikien
authors.forename: S C
authors.initials: SC
authors.lastname: Nagamani
authors.forename: C
authors.initials: C
authors.lastname: Lemons
authors.forename: B
authors.initials: B
authors.lastname: Lee
authors.forename: B F
authors.initials: BF
authors.lastname: Scharschmidt
mesh_terms: D015415:Biomarkers / Q000097:blood; D064420:Drug-Related Side Effects and Adverse Reactions / Q000097:blood / Q000209:etiology; D005973:Glutamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D005990:Glycerol / Q000008:administration & dosage / Q000031:analogs & derivatives; D006501:Hepatic Encephalopathy / Q000097:blood* / Q000209:etiology / Q000473:pathology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy; D010648:Phenylacetates / Q000008:administration & dosage / Q000097:blood*; D010654:Phenylbutyrates / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D056806:Urea Cycle Disorders, Inborn / Q000097:blood* / Q000453:epidemiology / Q000209:etiology / Q000473:pathology
chemical_list: D015415:Biomarkers; D010648:Phenylacetates; D010654:Phenylbutyrates; D005973:Glutamine; C003089:phenylacetylglutamine; C025136:phenylacetic acid; D005990:Glycerol; C570223:glycerol phenylbutyrate
keywords: BUPHENYL; GEE; GPB; Glycerol phenylbutyrate; HE; HPN-100; NaPBA; Neurological adverse events; PAA; PAA:PAGN ratio; PAGN; PBA; RAVICTI; SE; SO; Sodium phenylbutyrate; UCD; generalized estimating equations; glycerol phenylbutyrate (generic name for glyceryl tri (4-phenylbutyrate), also referred to as HPN-100 or RAVICTI(®)); hepatic encephalopathy; phenylacetic acid; phenylacetylglutamine; phenylbutyric acid; ratio of the concentrations in μg/mL of PAA to PAGN in plasma; safety extension; sodium phenylbutyrate (BUPHENYL(®)); switchover; urea cycle disorder