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

• Published in: Clinical and translational science 2022-06, Vol.15 (6), p.1449-1459
• Main Authors: Safadi, Rifaat, Rahimi, Robert S., Thabut, Dominique, Bajaj, Jasmohan S., Ram Bhamidimarri, Kalyan, Pyrsopoulos, Nikolaos, Potthoff, Amy, Bukofzer, Stan, Wang, Laurene, Jamil, Khurram, Devarakonda, Krishna R.
• Format: Article
• Language: English
• Subjects: Ammonia; Care and treatment; Cirrhosis; Cognition; Drug dosages; Hepatic encephalopathy; Hospital patients; Hospitalization; Human health and pathology; Hyperammonemia; Hépatology and Gastroenterology; Intravenous administration; Laboratories; Life Sciences; Liver; Liver cirrhosis; Liver diseases; Medical research; Medicine, Experimental; Metabolism; Metabolites; Metronidazole; Neomycin; Neurobiology; Neurons and Cognition; Ornithine; Patient outcomes; Patients; Pharmaceutical sciences; Pharmacodynamics; Pharmacokinetics; Pharmacology; Phenylacetic acid; Placebos; Plasma; Plasma levels; Rifaximin; Transplants & implants; Urine
• ISSN: 1752-8054; 1752-8062
• DOI: 10.1111/cts.13257

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 ~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.