Exposures of Phenylacetic Acid and Phenylacetylglutamine Across Different Subpopulations and Correlation with Adverse Events

Abstract

Background Elevated plasma ammonia is central to the pathogenesis of hepatic encephalopathy. Sodium phenylacetate or glycerol phenylbutyrate is approved for urea cycle disorders, but limited clinical data are available for hepatic encephalopathy. Phenylacetic acid (PAA) plasma exposure has been reported to correlate with neurologic adverse events in patients with cancer but not in patients with urea cycle disorders or hepatic encephalopathy. Ornithine phenylacetate, an intravenous dosage form of the l-ornithine salt of phenylacetate, is under development for hepatic encephalopathy. Objective This analysis summarized the pharmacokinetics and safety of ornithine phenylacetate to support the dosing strategy and to assist with the monitoring and management of neurologic adverse events in a global clinical development program. Methods Phenylacetic acid and phenylacetylglutamine (PAGN) pharmacokinetic data and adverse events from five clinical studies were included in the analysis. Hepatic and renal dysfunction were assessed by baseline Child-Pugh score and creatinine clearance, respectively. Predicted plasma exposures of PAA at the occurrence of neurologic adverse events were used for exposures and neurologic adverse event analysis. Results Phenylacetic acid exhibited nonlinear pharmacokinetics. Phenylacetic acid exposure was 35% higher in Child-Pugh C than in Child-Pugh B. No significant pharmacokinetic difference was identified between Caucasian and Asian subjects after body weight adjustment. Phenylacetylglutamine renal clearance decreased by five-fold in severe renal impairment compared with subjects with normal renal function. Renal dysfunction significantly elevated PAGN plasma concentrations; however, elevated PAGN due to reduced excretion of PAGN did not change PAA exposure and plasma ammonia levels. No correlation was observed between PAA plasma exposure and neurologic adverse events in patients with stable cirrhosis or acute hepatic encephalopathy. Conclusions Dose adjustment should be considered for patients with low body weight and severely impaired hepatic function. Phenylacetic acid plasma exposure was not correlated with neurologic adverse events in the ornithine phenylacetate target patient population.

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

“…Population PK modeling identified that PAA exposure was approximately 36% higher in patients with C-P C than in patients with C-P B. This derivation agreed with the observed PAA concentration at steady state from study HE209, where C-P C patients had a 35% higher exposure to PAA versus C-P B patients [8].…”

“…That renal dysfunction does not alter PAA exposure confirmed the hypothesis that the formation of PAGN is an irreversible process, thus the accumulation of PAGN in blood circulation due to reduced renal excretion would not alter the rate of PAGN formation. As such, renal dysfunction is not expected to change the removal of free ammonia in plasma circulation either, as observed from study HE209 [ 8 ]. To confirm this derivation, the present population PK model was applied to the PK data from a newly completed renal impairment study that included patients with severe renal impairment.…”

“…All participants gave written informed consent prior to the initiation of study procedures. Detailed information about the study design and results is provided in separate publications [8,12]. Brief information about the study designs is provided below.…”

“…Formulations that contain PAA or phenylbutyrate as the primary active moiety include sodium phenylbutyrate and glycerol phenylbutyrate and are approved for the acute and/or maintenance treatment of urea cycle disorders (UCD) [ 4 – 6 ]. Body size (weight or body surface area [BSA]) has a significant impact on PAA exposure [ 7 , 8 ]. The approved doses of sodium phenylbutyrate and glycerol phenylbutyrate are based on body weight or BSA [ 4 – 6 ].…”

“…The 15 g with 24 h of infusion in patients with C–P B or C–P C appeared to achieve comparable clinical efficacy compared to the 20 g with 24 h of infusion in patients with C–P B. In addition, PAA exposure at 20 g in C–P B was 36% higher than that in C–P C patients at 15 g, and no difference in adverse events was observed across different dose levels [ 8 , 12 ].…”