Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis


  • registration numbers: protocol UP 1204-001, ID# NCT00977600; protocol UP 1204-002, ID# NCT00986895. Studies for UP 1204-001 and UP 1204-002 provide assurance that informed consent in writing was obtained from each patient and the study protocols conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a prior approval by the appropriate institutional review committee.

  • Potential conflict of interest: K. Dickinson, A. Martinez, M. Mokhtarani, S. Gargosky, and B. F. Scharschmidt are employees of Hyperion or were at the time of the study. None of the other authors have a financial interest in Hyperion, although payments were made by Hyperion to Pharsight Corporation (Jon Monteleone), which performed the pharmacokinetic modeling, to University of Pittsburgh (Mark Lowe) for the studies of in vitro digestion of glycerol phenylbutyrate, and to the National University of Pharmacy and Kharkiv National Medical University, Kharkiv, Ukraine (Igor Zupanets, V. Syplyviy), where the clinical studies were conducted. Drs. McGuire, Monteleone, and Lowe are consultants for and received grants from Hypersion. Dr. Syplyviy received grants from Hypersion. Drs. Gargosky, Scharschmidt, Martinez, and Dickinson own stocks in Hypersion. Dr. Mokhtarani owns stock in Pfizer.


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 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 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. (HEPATOLOGY 2010;)