Glycerol phenylbutyrate ( Ravicti ) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine.
A randomized, double-blind, placebo-controlled phase II trial enrolled 178 patients with cirrhosis, including 59 already taking Rifaximin, who had experienced two or more hepatic encephalopathy events in the previous 6 months.
The primary endpoint was the proportion of patients with hepatic encephalopathy events. Other endpoints included the time to first event, total number of events, hepatic encephalopathy hospitalizations, symptomatic days, and safety.
Glycerol phenylbutyrate, at 6 mL orally twice-daily, significantly reduced the proportion of patients who experienced an hepatic encephalopathy event ( 21% versus 36%; P = 0.02 ), time to first event ( hazard ratio, HR= 0.56; P less than 0.05 ), as well as total events ( 35 versus 57; P = 0.04 ), and was associated with fewer hepatic encephalopathy hospitalizations ( 13 versus 25; P = 0.06 ).
Among patients not on Rifaximin at enrollment, Glycerol phenylbutyrate has reduced the proportion of patients with an hepatic encephalopathy event ( 10% versus 32%; P less than 0.01 ), time to first event ( HR = 0.29; P less than 0.01 ), and total events ( 7 versus 31; P less than 0.01 ).
Plasma ammonia was significantly lower in patients on Glycerol phenylbutyrate and correlated with hepatic encephalopathy events when measured either at baseline or during the study.
A similar proportion of patients in the GPB ( 79% ) and placebo groups ( 76% ) experienced adverse events.
In conclusion, Glycerol phenylbutyrate has reduced hepatic encephalopathy events as well as ammonia in patients with cirrhosis and hepatic encephalopathy, and its safety profile was similar to placebo.
The findings implicate ammonia in the pathogenesis of hepatic encephalopathy and suggest that Glycerol phenylbutyrate has therapeutic potential in this population. ( Xagena )
Rockey DC et al, Hepatology 2014; 59: 1073-1083