Glycerol phenylbutyrate for the chronic management of urea cycle disorders

Abstract

Glycerol phenylbutyrate (GPB) is a new generation ammonia scavenger drug that was recently approved by the US FDA for chronic management in patients with urea cycle defect disorders after multicenter clinical trials. GPB is composed of three molecules of phenylbutyrate (PB) that are esterified to a glycerol backbone. The active agent, phenylacetate, is generated through multiple metabolic steps including hydrolysis in the small intestine by pancreatic triglyceride lipases. Its pharmacokinetic pattern is characterized by a slower release of the active metabolite than unconjugated PB, which contributes to superior ammonia control and fewer episodes of hyperammonemia. GPB is well tolerated with fewer gastrointestinal complications compared with sodium benzoate or PB. These unique features suggest that it may enhance adherence and, potentially, in improved outcomes in urea cycle disorder patients. GPB may have therapeutic potential in additional conditions such as chronic hepatic encephalopathy or other inherited metabolic disorders.

Keywords::

• ammonia scavengers
• glycerol phenylbutyrate
• hyperammonemia
• inborn error of metabolism
• phenylacetate
• sodium phenylbutyrate
• urea cycle disorders

Financial & competing interests disclosure

K Oishi is an employee of the Icahn School of Medicine at Mount Sinai. GA. Diaz is an employee of the Icahn School of Medicine at Mount Sinai and received honoraria from Hyperion Therapeutics for participation on the Hyperion UCD National Advisory Board. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Glycerol phenylbutyrate (GPB) is a pre-prodrug to activate an alternative pathway to dispose of waste nitrogen for the chronic management of urea cycle disorders in children 2 years and older and in adults.

• GPB has to be used along with dietary protein restriction.

• GPB can be used in place of sodium phenylbutyrate for patients with poor compliance, with better drug tolerance seen in most patients.

• GPB treatment might result in better long-term ammonia control than sodium phenylbutyrate due to the slower release of the active metabolite, phenylacetate.

• GPB is not used for acute management of hyperammonemia.

Notes