Safety, Tolerability and Pharmacokinetics of L-Ornithine Phenylacetate in Patients with Acute Liver Injury/Failure and Hyperammonemia

Abstract

Cerebral edema remains a significant cause of morbidity and mortality in patients with acute liver failure (ALF) and has been linked to elevated blood ammonia levels. L-ornithine phenylacetate (OPA) may decrease ammonia by promoting its renal excretion as phenylacetylglutamine (PAGN), decreasing the risk of cerebral edema. We evaluated the safety, tolerability, and pharmacokinetics of OPA in patients with ALF and acute liver injury (ALI), including those with renal failure. Forty-seven patients with ALI/ALF and ammonia ≥60µM were enrolled. Patients received OPA in a dose escalation scheme from 3.3g/24h to 10g/24h; 15 patients received 20g/24h throughout the infusion for up to 120h. Plasma phenylacetate concentrations [PA] were uniformly below-target (<75µg/ml) in those receiving 3.3g/24h (median[IQR] 5.0[5.0]µg/ml), and increased to target levels in all but one who received 20g/24h (150[100]µg/ml). Plasma [PAGN] increased, and conversion of PA to PAGN became saturated, with increasing OPA dose. Urinary PAGN clearance and creatinine clearance were linearly related (r=0.831, P<0.0001). Mean ammonia concentrations based on the area-under-the-curve decreased to a greater extent in patients who received 20g/24h OPA compared to those who received the 3.3 or 6.7g/24h maximal dose (P=0.046 and 0.022, respectively). Of the reported serious adverse events (AEs) including 11 deaths, none were attributable to study medication. The only non-serious AEs possibly related to study drug were headache and nausea/vomiting. Conclusions. OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20g/24h, leading to ammonia excretion in urine as PAGN in proportion to renal function. Randomized, controlled studies of high-dose OPA are needed to determine its utility as an ammonia-scavenging agent in patients with ALF. This article is protected by copyright. All rights reserved.

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