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

Abstract

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.

Conflict of interest statement

R.S.: declares no competing interests for this work. R.S.R.: research support and an honorarium from Ocera Therapeutics (now Mallinckrodt Pharmaceuticals). D.T.: speaker for Norgine B.V. J.S.B.: institutional grant from Ocera Therapeutics and payment of personal fees during the conduct of the study; institutional grants from Valeant and Grifols; payment by Ocera and Norgine of personal fees for participation in an advisory board; payment by Valeant of personal fees. K.R.B.: grants from Gilead Sciences, Inc., Vital Therapies, and Mallinckrodt Pharmaceuticals; support as a member of the scientific advisory boards of Merck, Gilead, AbbVie, Inc., and Intercept Pharmaceuticals; and support from Alexion Pharmaceuticals, Inc., for providing disease state education. N.P.: research grants from Beigene, Intercept, Grifols, DURECT, Bayer, BMS, and Mallinckrodt Pharmaceuticals. A.P.: salary as an employee of Ocera Therapeutics at the time of the study. S.B.: salary as an employee of Ocera Therapeutics at the time of the study. L.W. received fees from Ocera Therapeutics for the design of this study and analysis of the pharmacokinetic data. K.J. is an employee of Mallinckrodt Pharmaceuticals. K.R.D. is a former employee of Mallinckrodt Pharmaceuticals who participated in the post hoc pharmacokinetic/pharmacodynamic analysis. The sponsor participated in the review of the manuscript (scientific accuracy and intellectual property only).

© 2022 Hadassah Medical Center. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1

Patient disposition flow diagram. aThe safety population (n = 226) included all patients who received any randomly assigned study treatment. bOnly one reason could be recorded per patient; if death was chosen as the reason, an adverse event could not be chosen as well. HE, hepatic encephalopathy; ITT, intention‐to‐treat; OP, ornithine phenylacetate; ULN, upper limit of normal

FIGURE 2

Mean (standard deviation) plasma levels and mean steady‐state plasma concentrations of (a) phenylacetic acid (PAA), (b) ornithine (ORN), and (c) phenylacetylglutamine (PAGN) following initiation of ORN infusion, by dose levela. aOnly 1 patient received 7 g/24 hours ornithine phenylacetate (OP) (not shown in the figure). Mean plasma levels of PAA, ORN, and PAGN for this patient were lower than those of the 10, 15, and 20 g/24 hours dose groups across all timepoints evaluated. Mean Css values for PAA, ORN, and PAGN after intravenous infusion of OP for this patient were 55.5, 17.9, and 22.2 μg/ml, respectively. Css, steady‐state plasma drug concentration; CV, coefficient of variation

FIGURE 3

Dose‐related mean reduction in plasma ammonia level from baseline to 3 hours after the end of infusion. aThe two‐sided p value comparing ornithine phenylacetate (OP) and placebo was based on a van Elteren test stratified by randomized strata

FIGURE 4

Kaplan–Meier analysis of time to achieve plasma ammonia levels less than or equal to upper limit of normal. Patients who died, had a liver transplant, or discontinued the study were censored. aThe two‐sided p value comparing ornithine phenylacetate and placebo is based on a log‐rank statistic, stratified by randomization strata. OP, ornithine phenylacetate; ULN, upper limit of normal

FIGURE 5

Correlation between plasma ammonia concentration reduction and clinical improvement at 48 hours. aThe two‐sided p value was calculated from an analysis of covariance model with a fixed effect for achieving versus not achieving primary clinical response, adjusting for the randomization strata