Safety, tolerability, and pharmacokinetics of l-ornithine phenylacetate in patients with acute liver injury/failure and hyperammonemia

for the Acute Liver Failure Study Group

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 ≥60 μM were enrolled. Patients received OPA in a dose escalation scheme from 3.3 g every 24 hours to 10 g every 24 hours; 15 patients received 20 g every 24 hours throughout the infusion for up to 120 hours. Plasma phenylacetate (PA) concentrations were uniformly below target (<75 μg/mL) in those receiving 3.3 g every 24 hours (median [interquartile range] 5.0 [5.0] μg/mL), and increased to target levels in all but one who received 20 g every 24 hours (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 20 g of OPA every 24 hours compared with those who received the maximal dose of 3.3 or 6.7 g every 24 hours (P = 0.046 and 0.022, respectively). Of the reported serious adverse events (AEs), which included 11 deaths, none was attributable to study medication. The only nonserious AEs possibly related to study drug were headache and nausea/vomiting. Conclusion: OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, 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 use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003–1013).

Original languageEnglish (US)
Pages (from-to)1003-1013
Number of pages11
JournalHepatology
Volume67
Issue number3
DOIs
StatePublished - Mar 1 2018

Fingerprint

Hyperammonemia
Acute Liver Failure
Ammonia
Pharmacokinetics
Safety
Wounds and Injuries
Brain Edema
Liver
Proxy
Gastroenterology
ornithine phenylacetate
Nausea
Area Under Curve
Vomiting
Renal Insufficiency
Headache
Creatinine
phenylacetylglutamine
Urine
Morbidity

ASJC Scopus subject areas

  • Hepatology

Cite this

@article{f9173438343b4e39a0c2388e298f7bae,
title = "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 ≥60 μM were enrolled. Patients received OPA in a dose escalation scheme from 3.3 g every 24 hours to 10 g every 24 hours; 15 patients received 20 g every 24 hours throughout the infusion for up to 120 hours. Plasma phenylacetate (PA) concentrations were uniformly below target (<75 μg/mL) in those receiving 3.3 g every 24 hours (median [interquartile range] 5.0 [5.0] μg/mL), and increased to target levels in all but one who received 20 g every 24 hours (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 20 g of OPA every 24 hours compared with those who received the maximal dose of 3.3 or 6.7 g every 24 hours (P = 0.046 and 0.022, respectively). Of the reported serious adverse events (AEs), which included 11 deaths, none was attributable to study medication. The only nonserious AEs possibly related to study drug were headache and nausea/vomiting. Conclusion: OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, 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 use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003–1013).",
author = "{for the Acute Liver Failure Study Group} and Stravitz, {R. Todd} and Michelle Gottfried and Valerie Durkalski and Fontana, {Robert J.} and Hanje, {A. James} and David Koch and Bilal Hameed and Ganger, {Daniel R} and Subramanian, {Ram M.} and Stan Bukofzer and Ravis, {William R.} and Kristen Clasen and Averell Sherker and Lanna Little and Lee, {William M.}",
year = "2018",
month = "3",
day = "1",
doi = "10.1002/hep.29621",
language = "English (US)",
volume = "67",
pages = "1003--1013",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

Safety, tolerability, and pharmacokinetics of l-ornithine phenylacetate in patients with acute liver injury/failure and hyperammonemia. / for the Acute Liver Failure Study Group.

In: Hepatology, Vol. 67, No. 3, 01.03.2018, p. 1003-1013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Safety, tolerability, and pharmacokinetics of l-ornithine phenylacetate in patients with acute liver injury/failure and hyperammonemia

AU - for the Acute Liver Failure Study Group

AU - Stravitz, R. Todd

AU - Gottfried, Michelle

AU - Durkalski, Valerie

AU - Fontana, Robert J.

AU - Hanje, A. James

AU - Koch, David

AU - Hameed, Bilal

AU - Ganger, Daniel R

AU - Subramanian, Ram M.

AU - Bukofzer, Stan

AU - Ravis, William R.

AU - Clasen, Kristen

AU - Sherker, Averell

AU - Little, Lanna

AU - Lee, William M.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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 ≥60 μM were enrolled. Patients received OPA in a dose escalation scheme from 3.3 g every 24 hours to 10 g every 24 hours; 15 patients received 20 g every 24 hours throughout the infusion for up to 120 hours. Plasma phenylacetate (PA) concentrations were uniformly below target (<75 μg/mL) in those receiving 3.3 g every 24 hours (median [interquartile range] 5.0 [5.0] μg/mL), and increased to target levels in all but one who received 20 g every 24 hours (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 20 g of OPA every 24 hours compared with those who received the maximal dose of 3.3 or 6.7 g every 24 hours (P = 0.046 and 0.022, respectively). Of the reported serious adverse events (AEs), which included 11 deaths, none was attributable to study medication. The only nonserious AEs possibly related to study drug were headache and nausea/vomiting. Conclusion: OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, 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 use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003–1013).

AB - 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 ≥60 μM were enrolled. Patients received OPA in a dose escalation scheme from 3.3 g every 24 hours to 10 g every 24 hours; 15 patients received 20 g every 24 hours throughout the infusion for up to 120 hours. Plasma phenylacetate (PA) concentrations were uniformly below target (<75 μg/mL) in those receiving 3.3 g every 24 hours (median [interquartile range] 5.0 [5.0] μg/mL), and increased to target levels in all but one who received 20 g every 24 hours (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 20 g of OPA every 24 hours compared with those who received the maximal dose of 3.3 or 6.7 g every 24 hours (P = 0.046 and 0.022, respectively). Of the reported serious adverse events (AEs), which included 11 deaths, none was attributable to study medication. The only nonserious AEs possibly related to study drug were headache and nausea/vomiting. Conclusion: OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, 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 use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003–1013).

UR - http://www.scopus.com/inward/record.url?scp=85041232176&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041232176&partnerID=8YFLogxK

U2 - 10.1002/hep.29621

DO - 10.1002/hep.29621

M3 - Article

VL - 67

SP - 1003

EP - 1013

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 3

ER -