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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01966419.

Conflict of interest statement

Xiaofeng Wang is a former employee of Mallinckrodt Pharmaceuticals. Regis A. Vilchez is a current employee of Mallinckrodt Pharmaceuticals. The study sponsor was involved in the study design and data collection, analysis, and interpretation.

© 2021. The Author(s).

Figures

Fig. 1

Schematic of the mechanism of action of l-ornithine and phenylacetate

Fig. 2

Schematic of the structural model for ornithine phenylacetate. Km Michaelis constant, ORN ornithine, PAA phenylacetic acid, PAGN phenylacetylglutamine, Vmax maximum rate

Fig. 3

A Final model diagnostic plots for phenylacetic acid in patients. CWRES conditional weighted residuals, DV observed data values, IPRED individual predictions, PRED population predictions. B Final model of conditional weighted residuals (CWRES) distribution and quantile-quantile (Q–Q) plot for phenylacetic acid in patients

Fig. 4

Visual predictive check for phenylacetic acid (PAA) in patients. CI confidence interval

Fig. 5

Simulated phenylacetic acid (PAA) exposure at the phase III dose or at the reduced dosing regimen. CP-B/C Child–Pugh class B or C. Dosing regimen except for the “CP-C_dose reduced”: day 1, 20 g infused over 6 h, 15 g infused over 18 h; day 2 to day 5, maintenance dose of 15 g infused over 24 h. CP-C_dose reduced: day 1, 15 g infused over 6 h, 10 g infused over 18 h; day 2 to day 5, maintenance dose of 10 g infused over 24 h. Solid lines: 5th, 50th, and 95th percentiles; dashed line: highest PAA concentration on the 95th percentile for Caucasians with CP-C at 20 g followed by a 15-g maintenance dose