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.