PMID- 24144944 OWN - NLM STAT- MEDLINE DCOM- 20140616 LR - 20211021 IS - 1096-7206 (Electronic) IS - 1096-7192 (Print) IS - 1096-7192 (Linking) VI - 110 IP - 4 DP - 2013 Dec TI - 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. PG - 446-53 LID - S1096-7192(13)00329-6 [pii] LID - 10.1016/j.ymgme.2013.09.017 [doi] AB - 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 mug/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 mug/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 mug/mL) in a random blood draw identified patients at risk for PAA levels>500 mug/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. CI - (c) 2013. FAU - Mokhtarani, M AU - Mokhtarani M AD - Hyperion Therapeutics, 601 Gateway Blvd., Suite 200, South San Francisco, CA 94080, USA. Electronic address: Masoud.mokhtarani@hyperiontx.com. FAU - Diaz, G A AU - Diaz GA FAU - Rhead, W AU - Rhead W FAU - Berry, S A AU - Berry SA FAU - Lichter-Konecki, U AU - Lichter-Konecki U FAU - Feigenbaum, A AU - Feigenbaum A FAU - Schulze, A AU - Schulze A FAU - Longo, N AU - Longo N FAU - Bartley, J AU - Bartley J FAU - Berquist, W AU - Berquist W FAU - Gallagher, R AU - Gallagher R FAU - Smith, W AU - Smith W FAU - McCandless, S E AU - McCandless SE FAU - Harding, C AU - Harding C FAU - Rockey, D C AU - Rockey DC FAU - Vierling, J M AU - Vierling JM FAU - Mantry, P AU - Mantry P FAU - Ghabril, M AU - Ghabril M FAU - Brown, R S Jr AU - Brown RS Jr FAU - Dickinson, K AU - Dickinson K FAU - Moors, T AU - Moors T FAU - Norris, C AU - Norris C FAU - Coakley, D AU - Coakley D FAU - Milikien, D A AU - Milikien DA FAU - Nagamani, S C AU - Nagamani SC FAU - Lemons, C AU - Lemons C FAU - Lee, B AU - Lee B FAU - Scharschmidt, B F AU - Scharschmidt BF LA - eng SI - ClinicalTrials.gov/NCT00551200 SI - ClinicalTrials.gov/NCT00947297 SI - ClinicalTrials.gov/NCT00947544 SI - ClinicalTrials.gov/NCT00992459 SI - ClinicalTrials.gov/NCT00999167 SI - ClinicalTrials.gov/NCT01347073 GR - UL1 RR033176/RR/NCRR NIH HHS/United States GR - UL1 RR024989/RR/NCRR NIH HHS/United States GR - UL1RR25780/RR/NCRR NIH HHS/United States GR - UL1 RR025752/RR/NCRR NIH HHS/United States GR - UL1 TR000114/TR/NCATS NIH HHS/United States GR - UL1TR000005/TR/NCATS NIH HHS/United States GR - UL1RR25744/RR/NCRR NIH HHS/United States GR - UL1 RR031988/RR/NCRR NIH HHS/United States GR - UL1 RR025014/RR/NCRR NIH HHS/United States GR - UL1RR25014/RR/NCRR NIH HHS/United States GR - UL1RR25764/RR/NCRR NIH HHS/United States GR - UL1RR33176/RR/NCRR NIH HHS/United States GR - M01RR00188/RR/NCRR NIH HHS/United States GR - UL1RR24153/RR/NCRR NIH HHS/United States GR - UL1 TR000005/TR/NCATS NIH HHS/United States GR - UL1RR29890/RR/NCRR NIH HHS/United States GR - UL1RR33183/RR/NCRR NIH HHS/United States GR - UL1 RR033183/RR/NCRR NIH HHS/United States GR - UL1 RR024153/RR/NCRR NIH HHS/United States GR - UL1 RR029890/RR/NCRR NIH HHS/United States GR - UL1RR25752/RR/NCRR NIH HHS/United States GR - UL1 RR025764/RR/NCRR NIH HHS/United States GR - UL1RR31988/RR/NCRR NIH HHS/United States GR - UL1RR24140/RR/NCRR NIH HHS/United States GR - UL1 RR025780/RR/NCRR NIH HHS/United States GR - M01 RR000188/RR/NCRR NIH HHS/United States GR - U54RR019453/RR/NCRR NIH HHS/United States GR - U54 HD061221/HD/NICHD NIH HHS/United States GR - UL1 RR025744/RR/NCRR NIH HHS/United States GR - UL1RR024989/RR/NCRR NIH HHS/United States GR - UL1 TR001085/TR/NCATS NIH HHS/United States GR - U54 RR019453/RR/NCRR NIH HHS/United States GR - UL1 RR031973/RR/NCRR NIH HHS/United States GR - UL1 TR001082/TR/NCATS NIH HHS/United States GR - UL1 RR029887/RR/NCRR NIH HHS/United States GR - UL1RR31973/RR/NCRR NIH HHS/United States GR - UL1 RR024140/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20131008 PL - United States TA - Mol Genet Metab JT - Molecular genetics and metabolism JID - 9805456 RN - 0 (Biomarkers) RN - 0 (Phenylacetates) RN - 0 (Phenylbutyrates) RN - 0RH81L854J (Glutamine) RN - 92358I79RG (phenylacetylglutamine) RN - ER5I1W795A (phenylacetic acid) RN - PDC6A3C0OX (Glycerol) RN - ZH6F1VCV7B (glycerol phenylbutyrate) SB - IM MH - Biomarkers/blood MH - Drug-Related Side Effects and Adverse Reactions/blood/etiology MH - Glutamine/administration & dosage/*analogs & derivatives/blood MH - Glycerol/administration & dosage/analogs & derivatives MH - Hepatic Encephalopathy/*blood/etiology/pathology MH - Humans MH - Liver/drug effects/metabolism MH - Neoplasms/complications/drug therapy MH - Phenylacetates/administration & dosage/*blood MH - Phenylbutyrates/administration & dosage MH - Randomized Controlled Trials as Topic MH - Urea Cycle Disorders, Inborn/*blood/epidemiology/etiology/pathology PMC - PMC4108288 MID - NIHMS577198 OTO - NOTNLM OT - BUPHENYL OT - GEE OT - GPB OT - Glycerol phenylbutyrate OT - HE OT - HPN-100 OT - NaPBA OT - Neurological adverse events OT - PAA OT - PAA:PAGN ratio OT - PAGN OT - PBA OT - RAVICTI OT - SE OT - SO OT - Sodium phenylbutyrate OT - UCD OT - generalized estimating equations OT - glycerol phenylbutyrate (generic name for glyceryl tri (4-phenylbutyrate), also referred to as HPN-100 or RAVICTI((R))) OT - hepatic encephalopathy OT - phenylacetic acid OT - phenylacetylglutamine OT - phenylbutyric acid OT - ratio of the concentrations in mug/mL of PAA to PAGN in plasma OT - safety extension OT - sodium phenylbutyrate (BUPHENYL((R))) OT - switchover OT - urea cycle disorder EDAT- 2013/10/23 06:00 MHDA- 2014/06/17 06:00 PMCR- 2014/12/01 CRDT- 2013/10/23 06:00 PHST- 2013/09/26 00:00 [received] PHST- 2013/09/29 00:00 [accepted] PHST- 2013/10/23 06:00 [entrez] PHST- 2013/10/23 06:00 [pubmed] PHST- 2014/06/17 06:00 [medline] PHST- 2014/12/01 00:00 [pmc-release] AID - S1096-7192(13)00329-6 [pii] AID - 10.1016/j.ymgme.2013.09.017 [doi] PST - ppublish SO - Mol Genet Metab. 2013 Dec;110(4):446-53. doi: 10.1016/j.ymgme.2013.09.017. Epub 2013 Oct 8.