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

• Published in: Molecular genetics and metabolism Vol. 110; no. 4; pp. 446 - 453
• Main Authors: Mokhtarani, M., Diaz, G.A., Rhead, W., Berry, S.A., Lichter-Konecki, U., Feigenbaum, A., Schulze, A., Longo, N., Bartley, J., Berquist, W., Gallagher, R., Smith, W., McCandless, S.E., Harding, C., Rockey, D.C., Vierling, J.M., Mantry, P., Ghabril, M., Brown, R.S., Dickinson, K., Moors, T., Norris, C., Coakley, D., Milikien, D.A., Nagamani, S.C., LeMons, C., Lee, B., Scharschmidt, B.F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2013
• Subjects: Biomarkers - blood; BUPHENYL; Drug-Related Side Effects and Adverse Reactions - blood; Drug-Related Side Effects and Adverse Reactions - etiology; Glutamine - administration & dosage; Glutamine - analogs & derivatives; Glutamine - blood; Glycerol - administration & dosage; Glycerol - analogs & derivatives; Glycerol phenylbutyrate; Hepatic Encephalopathy - blood; Hepatic Encephalopathy - etiology; Hepatic Encephalopathy - pathology; HPN-100; Humans; Liver - drug effects; Liver - metabolism; Neoplasms - complications; Neoplasms - drug therapy; Neurological adverse events; Phenylacetates - administration & dosage; Phenylacetates - blood; Phenylbutyrates - administration & dosage; Randomized Controlled Trials as Topic; RAVICTI; Sodium phenylbutyrate; Urea Cycle Disorders, Inborn - blood; Urea Cycle Disorders, Inborn - epidemiology; Urea Cycle Disorders, Inborn - etiology; Urea Cycle Disorders, Inborn - pathology; NaPBA; GEE; Neurological adverse events; PBA; HPN-100; PAA; Sodium phenylbutyrate; SE; PAA:PAGN ratio; UCD; GPB; Glycerol phenylbutyrate; SO; HE; PAGN; BUPHENYL; RAVICTI; generalized estimating equations; safety extension; switchover; hepatic encephalopathy; phenylacetylglutamine; sodium phenylbutyrate (BUPHENYL(®)); phenylbutyric acid; urea cycle disorder; ratio of the concentrations in μg/mL of PAA to PAGN in plasma; phenylacetic acid; glycerol phenylbutyrate (generic name for glyceryl tri (4-phenylbutyrate), also referred to as HPN-100 or RAVICTI(®))
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2013.09.017

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≥500μg/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. 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 ≥2months 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. Only 0.2% (11) of 4683 samples exceeded 500μg/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>500μg/ml. 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. •Plasma PAA levels>500μg/dl associated with neurological AE in cancer patients.•Investigated trend of PAA and neurological AE in patients treated with PAA pro-drug.•Neurological AEs are transient in patients treated with PAA pro-drug.•High plasma PAA/PAGN identified patients are at risk for high PAA levels.•No correlation was found in patients between PAA levels and neurological AEs.