Glycerol Phenylbutyrate (Ravicti) [Internet]

Excerpt

Urea cycle disorders (UCDs) result from genetic mutations that cause defects in any of the five enzymes of the urea cycle in the liver: carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase, and arginase; in the co-factor producer N-acetyl glutamate synthetase; or in the ornithine transporter and citrin. The estimated incidence of UCDs ranges from one in 22,179 births to one in 53,717 births. The most recent estimate of incidence of UCDs for the US is around one in 35,000 births. It is estimated that approximately 11 new cases of UCDs will be diagnosed each year in Canada. The incidence of OTC deficiency (one in 56,500 live births) is higher than other UCDs. Deficiencies in the urea cycle may result in excessive ammonia levels due to impaired metabolism, which can be life-threatening and result in permanent neurological damage if left untreated. Treatment should be initiated as soon as a diagnosis of a UCD is suspected and should proceed simultaneously with the diagnostic evaluation.

The goals of long-term management of UCDs are to achieve normal development, to prevent hyperammonemia, and to maintain a good quality of life (QoL). These are achieved through a low-protein diet (and sometimes essential amino acids and other essential nutrients supplementation), pharmacotherapies to increase waste nitrogen excretion, and liver transplantation in selected patients. Sodium phenylbutyrate (NaPBA) is the mainstay of pharmacological therapy in chronic management of UCDs; however, its use is associated with decreased appetite, taste disturbances, body odour and menstrual dysfunction/amenorrhea. More recently, glycerol phenylbutyrate (GPB, brand name Ravicti) was approved as a nitrogen-scavenging therapy. This is a triglyceride containing three molecules of phenylbutyric acid. Its major metabolite, phenylacetic acid, conjugates with glutamine through acetylation in the liver and kidneys to form phenylacetylglutamine, which is excreted by the kidneys. GPB is administered orally with a recommended total dose ranging from 4.5 mL/m² per day to 11.2 mL/m² per day (5.0 g/m² per day to 12.4 g/m² per day). For patients who have been previously treated with NaPBA, the total daily dose of GPB can be calculated based on the total daily dose of NaPBA.

The objective of this systematic review is to examine the beneficial and harmful effects of GPB as a nitrogen-binding agent adjunctive to dietary protein restriction and dietary supplements for chronic management of adult and pediatric (at least two years of age) patients with UCDs.