PMID- 29080224
OWN - NLM
STAT- MEDLINE
DCOM- 20181011
LR  - 20231112
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 67
IP  - 3
DP  - 2018 Mar
TI  - Safety, tolerability, and pharmacokinetics of l-ornithine phenylacetate in 
      patients with acute liver injury/failure and hyperammonemia.
PG  - 1003-1013
LID - 10.1002/hep.29621 [doi]
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 muM 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 mug/mL) in those receiving 3.3 g every 24 hours 
      (median [interquartile range] 5.0 [5.0] mug/mL), and increased to target levels in 
      all but one who received 20 g every 24 hours (150 [100] mug/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).
CI  - (c) 2017 by the American Association for the Study of Liver Diseases.
FAU - Stravitz, R Todd
AU  - Stravitz RT
AD  - Virginia Commonwealth University, Richmond, VA.
FAU - Gottfried, Michelle
AU  - Gottfried M
AD  - Medical University of South Carolina, Charleston, SC.
FAU - Durkalski, Valerie
AU  - Durkalski V
AD  - Medical University of South Carolina, Charleston, SC.
FAU - Fontana, Robert J
AU  - Fontana RJ
AD  - University of Michigan, Ann Arbor, MI.
FAU - Hanje, A James
AU  - Hanje AJ
AD  - Ohio State University, Columbus, OH.
FAU - Koch, David
AU  - Koch D
AD  - Medical University of South Carolina, Charleston, SC.
FAU - Hameed, Bilal
AU  - Hameed B
AD  - University of California at San Francisco, San Francisco, CA.
FAU - Ganger, Daniel
AU  - Ganger D
AD  - Northwestern University, Chicago, IL.
FAU - Subramanian, Ram M
AU  - Subramanian RM
AD  - Emory University, Atlanta, GA.
FAU - Bukofzer, Stan
AU  - Bukofzer S
AD  - Ocera Therapeutics, Durham, NC.
FAU - Ravis, William R
AU  - Ravis WR
AD  - Auburn University, Tuscaloosa, AL.
FAU - Clasen, Kristen
AU  - Clasen K
AD  - Medical University of South Carolina, Charleston, SC.
FAU - Sherker, Averell
AU  - Sherker A
AD  - National Institute of Diabetes, Digestive and Kidney Disease, Bethesda, MD.
FAU - Little, Lanna
AU  - Little L
AD  - University of Texas, Southwestern Medical Center, Dallas, TX.
FAU - Lee, William M
AU  - Lee WM
AUID- ORCID: 0000-0002-2783-5441
AD  - University of Texas, Southwestern Medical Center, Dallas, TX.
CN  - Acute Liver Failure Study Group
LA  - eng
GR  - R01 DK058369/DK/NIDDK NIH HHS/United States
GR  - U01 DK058369/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180130
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Acetates)
RN  - 0 (Phenols)
RN  - 0RH81L854J (Glutamine)
RN  - 355G9R500Y (phenyl acetate)
RN  - 7664-41-7 (Ammonia)
RN  - 92358I79RG (phenylacetylglutamine)
RN  - 9D6YZ105SN (ornithine phenylacetate)
RN  - E524N2IXA3 (Ornithine)
SB  - IM
MH  - Acetates/blood
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Ammonia/blood
MH  - Female
MH  - Glutamine/analogs & derivatives/metabolism
MH  - Humans
MH  - Hyperammonemia/complications/*drug therapy
MH  - Kidney Function Tests
MH  - Liver/pathology
MH  - Liver Failure, Acute/complications/*drug therapy
MH  - Male
MH  - Middle Aged
MH  - Ornithine/administration & dosage/adverse effects/*analogs & 
      derivatives/pharmacokinetics
MH  - Phenols/blood
MH  - Registries
MH  - Treatment Outcome
MH  - Young Adult
PMC - PMC5826861
MID - NIHMS921303
EDAT- 2017/10/29 06:00
MHDA- 2018/10/12 06:00
PMCR- 2019/03/01
CRDT- 2017/10/29 06:00
PHST- 2017/06/11 00:00 [received]
PHST- 2017/08/03 00:00 [revised]
PHST- 2017/10/25 00:00 [accepted]
PHST- 2017/10/29 06:00 [pubmed]
PHST- 2018/10/12 06:00 [medline]
PHST- 2017/10/29 06:00 [entrez]
PHST- 2019/03/01 00:00 [pmc-release]
AID - 10.1002/hep.29621 [doi]
PST - ppublish
SO  - Hepatology. 2018 Mar;67(3):1003-1013. doi: 10.1002/hep.29621. Epub 2018 Jan 30.