Population Pharmacokinetic Analysis to Assist Dose Selection of the l-Ornithine Salt of Phenylacetic Acid

BACKGROUND AND OBJECTIVE: l-Ornithine phenylacetate is an intravenous formulation of the l-ornithine salt of phenylacetic acid under development for the treatment of hepatic encephalopathy. Very limited clinical data in patients are available, with a phase II study in target patients not designed for dose finding, to support phase III dose selection in a global development program. The objective of the present population pharmacokinetic modeling and simulation was to evaluate dose selection for target patient populations with a low body weight, ethnicity, and hepatic impairment in a global clinical study. METHODS: A population pharmacokinetic model was developed based on plasma concentrations of l-ornithine, phenylacetic acid, and phenylacetylglutamine data from four clinical trials in healthy subjects and patients with stable cirrhosis or hospitalized adult patients with liver cirrhosis and hepatic encephalopathy. A covariate analysis was conducted to identify source of variability to support dose selection for global clinical development of l-ornithine phenylacetate. Phenylacetylglutamine formation in the pharmacokinetic model also quantified pharmacodynamic effects measured by ammonia removal. RESULTS: Body weight and hepatic function were significant covariates determining phenylacetic acid exposure. After accounting for body weight, there was no difference between tested Caucasian and Asian populations in phenylacetic acid exposure. Renal dysfunction significantly reduced phenylacetylglutamine excretion. However, renal impairment had no impact on plasma phenylacetic acid and free ammonia levels. Exploratory modeling suggested that l-ornithine might enhance the removal of ammonia. CONCLUSIONS: With a flat dosing algorithm, special consideration must be given to patients with a small body size (i.e., body weight ≤ 50 kg) and severe hepatic impairment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-021-01075-1.