Glycerol phenylbutyrate in patients with cirrhosis and episodic hepatic encephalopathy: A pilot study of safety and effect on venous ammonia concentration

Marwan Ghabril, Igor A. Zupanets, John Vierling, Parvez Mantry, Don Rockey, David Wolf, Robert O'Shea, Klara Dickinson, Heather Gillaspy, Catherine Norris, Dion F. Coakley, Masoud Mokhtarani, Bruce F. Scharschmidt

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Glycerol tri-(4-phenylbutyrate) (glycerol phenylbutyrate, GPB, HPN-100) mediates waste nitrogen excretion through conjugation with glutamine to form phenylacetylglutamine which is excreted in urine. This pilot study was performed to assess tolerability and effect on venous ammonia concentration in patients with cirrhosis and hepatic encephalopathy (HE). Patients underwent one week of 6mL (6.6g) twice daily (BID). GPB dosing followed by 3 weeks of 9 mL (9.9g) BID dosing and underwent repeated blood sampling for ammonia concentration and pharmacokinetics. Fifteen patients were enrolled. Ammonia concentrations were lowest after overnight fast and increased post-prandially. Fasting ammonia concentrations were lower on GPB compared to baseline, with a decrease on the eighth day of 6mL BID dosing to 45.4 (27.9)μmol/L (ULN ∼48 μmol/L) (P<.05). Nine milliliters BID yielded similar lowering but was associated with more adverse events and higher phenylacetate (PAA) plasma concentrations (PAACmax of 144 [125] vs. 292 [224]μg/mL on 6 and 9mL, respectively). GPB dosed at 6mL BID lowered fasting ammonia levels in cirrhotic patients with HE as compared with baseline, was better tolerated than 9mL BID, and is appropriate for further evaluation in patients with cirrhosis and episodic HE.

Original languageEnglish (US)
Pages (from-to)278-284
Number of pages7
JournalClinical Pharmacology in Drug Development
Volume2
Issue number3
DOIs
StatePublished - Jul 1 2013

Keywords

  • Ammonia
  • Cirrhosis
  • Hepatic encephalopathy
  • Phenylacetylglutamine
  • Phenylbutyrate

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmaceutical Science

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    Ghabril, M., Zupanets, I. A., Vierling, J., Mantry, P., Rockey, D., Wolf, D., O'Shea, R., Dickinson, K., Gillaspy, H., Norris, C., Coakley, D. F., Mokhtarani, M., & Scharschmidt, B. F. (2013). Glycerol phenylbutyrate in patients with cirrhosis and episodic hepatic encephalopathy: A pilot study of safety and effect on venous ammonia concentration. Clinical Pharmacology in Drug Development, 2(3), 278-284. https://doi.org/10.1002/cpdd.18