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

11 Citations (Scopus)

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

Fingerprint

Hepatic Encephalopathy
Ammonia
Fibrosis
Safety
Fasting
Glutamine
Glycerol
Nitrogen
Pharmacokinetics
glycerol phenylbutyrate
Urine

Keywords

  • Ammonia
  • Cirrhosis
  • Hepatic encephalopathy
  • Phenylacetylglutamine
  • Phenylbutyrate

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmaceutical Science

Cite this

Glycerol phenylbutyrate in patients with cirrhosis and episodic hepatic encephalopathy : A pilot study of safety and effect on venous ammonia concentration. / Ghabril, Marwan; Zupanets, Igor A.; Vierling, John; Mantry, Parvez; Rockey, Don; Wolf, David; O'Shea, Robert; Dickinson, Klara; Gillaspy, Heather; Norris, Catherine; Coakley, Dion F.; Mokhtarani, Masoud; Scharschmidt, Bruce F.

In: Clinical Pharmacology in Drug Development, Vol. 2, No. 3, 07.2013, p. 278-284.

Research output: Contribution to journalArticle

Ghabril, M, Zupanets, IA, Vierling, J, Mantry, P, Rockey, D, Wolf, D, O'Shea, R, Dickinson, K, Gillaspy, H, Norris, C, Coakley, DF, Mokhtarani, M & Scharschmidt, BF 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, vol. 2, no. 3, pp. 278-284. https://doi.org/10.1002/cpdd.18
Ghabril, Marwan ; Zupanets, Igor A. ; Vierling, John ; Mantry, Parvez ; Rockey, Don ; Wolf, David ; O'Shea, Robert ; Dickinson, Klara ; Gillaspy, Heather ; Norris, Catherine ; Coakley, Dion F. ; Mokhtarani, Masoud ; Scharschmidt, Bruce F. / Glycerol phenylbutyrate in patients with cirrhosis and episodic hepatic encephalopathy : A pilot study of safety and effect on venous ammonia concentration. In: Clinical Pharmacology in Drug Development. 2013 ; Vol. 2, No. 3. pp. 278-284.
@article{1988566e362048478c3fbce1fe3b989c,
title = "Glycerol phenylbutyrate in patients with cirrhosis and episodic hepatic encephalopathy: A pilot study of safety and effect on venous ammonia concentration",
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.",
keywords = "Ammonia, Cirrhosis, Hepatic encephalopathy, Phenylacetylglutamine, Phenylbutyrate",
author = "Marwan Ghabril and Zupanets, {Igor A.} and John Vierling and Parvez Mantry and Don Rockey and David Wolf and Robert O'Shea and Klara Dickinson and Heather Gillaspy and Catherine Norris and Coakley, {Dion F.} and Masoud Mokhtarani and Scharschmidt, {Bruce F.}",
year = "2013",
month = "7",
doi = "10.1002/cpdd.18",
language = "English",
volume = "2",
pages = "278--284",
journal = "Clinical Pharmacology in Drug Development",
issn = "2160-763X",
publisher = "Sage Periodicals Press",
number = "3",

}

TY - JOUR

T1 - Glycerol phenylbutyrate in patients with cirrhosis and episodic hepatic encephalopathy

T2 - A pilot study of safety and effect on venous ammonia concentration

AU - Ghabril, Marwan

AU - Zupanets, Igor A.

AU - Vierling, John

AU - Mantry, Parvez

AU - Rockey, Don

AU - Wolf, David

AU - O'Shea, Robert

AU - Dickinson, Klara

AU - Gillaspy, Heather

AU - Norris, Catherine

AU - Coakley, Dion F.

AU - Mokhtarani, Masoud

AU - Scharschmidt, Bruce F.

PY - 2013/7

Y1 - 2013/7

N2 - 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.

AB - 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.

KW - Ammonia

KW - Cirrhosis

KW - Hepatic encephalopathy

KW - Phenylacetylglutamine

KW - Phenylbutyrate

UR - http://www.scopus.com/inward/record.url?scp=84892488882&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892488882&partnerID=8YFLogxK

U2 - 10.1002/cpdd.18

DO - 10.1002/cpdd.18

M3 - Article

AN - SCOPUS:84892488882

VL - 2

SP - 278

EP - 284

JO - Clinical Pharmacology in Drug Development

JF - Clinical Pharmacology in Drug Development

SN - 2160-763X

IS - 3

ER -