UNLABELLED: Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBAand eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by human pancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. CONCLUSION:GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted.
RCT Entities:
UNLABELLED: Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derivedphenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBA and eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by humanpancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. CONCLUSION:GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted.
Authors: G Boehm; U Bierbach; H Senger; I Jakobsson; I Minoli; G Moro; N C Räihä Journal: J Pediatr Gastroenterol Nutr Date: 1991-04 Impact factor: 2.839
Authors: R Todd Stravitz; Michelle Gottfried; Valerie Durkalski; Robert J Fontana; A James Hanje; David Koch; Bilal Hameed; Daniel Ganger; Ram M Subramanian; Stan Bukofzer; William R Ravis; Kristen Clasen; Averell Sherker; Lanna Little; William M Lee Journal: Hepatology Date: 2018-01-30 Impact factor: 17.425
Authors: Uta Lichter-Konecki; G A Diaz; J L Merritt; A Feigenbaum; C Jomphe; J F Marier; M Beliveau; J Mauney; K Dickinson; A Martinez; M Mokhtarani; B Scharschmidt; W Rhead Journal: Mol Genet Metab Date: 2011-05-05 Impact factor: 4.797
Authors: Wendy Smith; George A Diaz; Uta Lichter-Konecki; Susan A Berry; Cary O Harding; Shawn E McCandless; Cindy LeMons; Joe Mauney; Klara Dickinson; Dion F Coakley; Tristen Moors; Masoud Mokhtarani; Bruce F Scharschmidt; Brendan Lee Journal: J Pediatr Date: 2013-01-13 Impact factor: 4.406
Authors: George A Diaz; Lauren S Krivitzky; Masoud Mokhtarani; William Rhead; James Bartley; Annette Feigenbaum; Nicola Longo; William Berquist; Susan A Berry; Renata Gallagher; Uta Lichter-Konecki; Dennis Bartholomew; Cary O Harding; Stephen Cederbaum; Shawn E McCandless; Wendy Smith; Gerald Vockley; Stephen A Bart; Mark S Korson; David Kronn; Roberto Zori; J Lawrence Merritt; Sandesh C S Nagamani; Joseph Mauney; Cynthia Lemons; Klara Dickinson; Tristen L Moors; Dion F Coakley; Bruce F Scharschmidt; Brendan Lee Journal: Hepatology Date: 2013-01-03 Impact factor: 17.425