Pharmacokinetics/pharmacodynamics of L-ornithine phenylacetate in overt hepatic encephalopathy and the effect of plasma ammonia concentration reduction on clinical outcomes

Hepatic encephalopathy (HE) is a serious neurocognitive complication of liver dysfunction, often associated with elevated plasma ammonia. Ornithine phenylacetate (OP), a potent ammonia scavenger, is being evaluated for the treatment of acute/overt HE. The pharmacokinetics and pharmacodynamics of OP in patients with HE were characterized in this phase IIb study (NCT01966419). Adult patients hospitalized with an overt HE episode, cirrhosis, and plasma ammonia above the upper limit of normal (ULN) who failed to improve after 48 hours' standard care were randomly assigned to continuous intravenous OP (10, 15, or 20 g/day, based on Child-Turcotte-Pugh score) or matching placebo for 5 days. Plasma levels of ornithine and phenylacetic acid (PAA) and plasma/urinary levels of phenylacetylglutamine (PAGN) (primary metabolite of PAA) were regularly assessed; plasma ammonia level was the primary pharmacodynamic variable. PAA demonstrated dose-dependent pharmacokinetics; ornithine and PAGN levels increased with dose. PAGN urinary excretion represented similar to 50%-60% of administered PAA across all doses. Mean reduction in plasma ammonia with OP at 3 hours postinfusion was significantly greater versus placebo (p = 0.014); and time to achieve plasma ammonia less than or equal to the ULN was significantly reduced (p = 0.028). Achievement of clinical response based on HE stage was associated with a greater reduction in mean plasma ammonia level (p = 0.009). OP effects on plasma ammonia were consistent with its proposed mechanism of action as a primary ammonia scavenger, with a significant association between reduced plasma ammonia and improvement in HE stage. OP should be further evaluated as a promising treatment for hyperammonemia in patients with overt HE. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Overt hepatic encephalopathy (OHE) is characterized by severe liver impairment and signs of neurocognitive dysfunction commonly associated with hyperammonemia. Ornithine phenylacetate (OP), a potent ammonia scavenger, has an acceptable safety profile in patients with decompensated cirrhosis and gastrointestinal bleeding, and lowers plasma ammonia levels. WHAT QUESTION DID THIS STUDY ADDRESS? What are the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of OP and its metabolites in patients hospitalized due to OHE with cirrhosis and hyperammonemia? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? PK/PD analysis results are consistent with the putative mechanism of action of OP. Mean plasma levels of OP analytes reach steady state in approximately 48-72 hours, regardless of dose, and appear to increase as liver function declines. OP treatment significantly reduces plasma ammonia and improves clinical OHE stage, supporting the proposed central role of ammonia in HE. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? OP treatment may be beneficial as a first-line treatment for patients with OHE; however, additional studies are warranted.