title: Absence of Liver Toxicity in Perampanel-Treated Subjects: Pooled results from partial seizure phase III perampanel clinical studies.
abstract: OBJECTIVE
  The liver plays a major role in the metabolism and elimination of many antiepileptic drugs (AEDs), including perampanel. Some of the metabolites identified for perampanel are likely formed via reactive intermediates, which have the potential to covalently bind to protein and cause idiosyncratic toxicities, including hepatotoxicity. The approved AED perampanel is a selective, noncompetitive AMPA receptor antagonist. The safety and tolerability of perampanel have been well documented in 3 double-blind, randomized, placebo-controlled, phase III studies. Here we report the effects of perampanel on liver function in patients from the phase III studies to assess the potential for liver toxicity.
  
  
  METHODS
  Following 6-week baseline, patients (≥12 years old) with drug-resistant partial seizures were randomized to once-daily double-blind treatment (6-week titration, 13-week maintenance) with 2, 4, 8, or 12mg perampanel (n=1038) or with placebo (n=442). Clinical laboratory tests for hepatobiliary laboratory parameters were evaluated at baseline and at end of treatment. These included alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transpeptidase, and total bilirubin. Treatment-emergent markedly abnormal values (an increase in NCI-CTC grade relative to baseline and a grade ≥2) and treatment-emergent adverse events (TEAEs) related to hepatobiliary parameters were also recorded.
  
  
  RESULTS
  Mean hepatobiliary values were within normal ranges at baseline and end of treatment for all perampanel groups and placebo. Mean changes from baseline to end of treatment were small. The incidence of markedly abnormal results was very low for perampanel and placebo. TEAEs related to hepatobiliary parameters occurred in 0.4% of perampanel patients and 0% of placebo patients. Hepatobiliary disorders included cholelithiasis (n=3 in perampanel) and abnormal hepatic function (n=1 in perampanel). None of the events were serious or led to perampanel discontinuation. No subject had values that met the criteria for Hy's Law.
  
  
  CONCLUSIONS
  Hepatobiliary laboratory data and related TEAEs were not notably different between perampanel and placebo treatment groups, and no dose-related trends were observed. Based on the laboratory results from the 3 Phase III studies, perampanel (2, 4, 8, and 12mg) demonstrated no clinically important effects on liver function tests, indicating perampanel is an AED with a low potential for drug-induced liver toxicity.
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Eisai Inc., 155 Tice Blvd., Woodcliff Lake, NJ 07677, USA. Electronic address: Antonio_Laurenza@eisai.com.
authors.forename: Antonio
authors.initials: A
authors.lastname: Laurenza
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Eisai Inc., 155 Tice Blvd., Woodcliff Lake, NJ 07677, USA. Electronic address: Haichen_Yang@eisai.com.
authors.forename: Haichen
authors.initials: H
authors.lastname: Yang
authors.affiliation: Eisai Medical and Scientific Affairs, Eisai Inc., 100 Tice Blvd., Woodcliff Lake, NJ 07677, USA. Electronic address: betsy_williams@eisai.com.
authors.forename: Betsy
authors.initials: B
authors.lastname: Williams
authors.affiliation: Eisai Medical and Scientific Affairs, Eisai Inc., 100 Tice Blvd., Woodcliff Lake, NJ 07677, USA. Electronic address: Xiaozheng_Zhou@eisai.com.
authors.forename: Sharon
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Eisai Inc., 155 Tice Blvd., Woodcliff Lake, NJ 07677, USA. Electronic address: Jim_Ferry@eisai.com.
authors.forename: Jim
authors.initials: J
authors.lastname: Ferry
mesh_terms: D000293:Adolescent; D000328:Adult; D000469:Alkaline Phosphatase / Q000378:metabolism; D000927:Anticonvulsants / Q000097:blood / Q000627:therapeutic use*; D018826:CD13 Antigens / Q000378:metabolism; D017326:Clinical Trials, Phase III as Topic; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004828:Epilepsies, Partial / Q000097:blood / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D043384:Glutamyl Aminopeptidase / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008111:Liver Function Tests; D008297:Male; D015337:Multicenter Studies as Topic; D009570:Nitriles; D011728:Pyridones / Q000097:blood / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; D005723:gamma-Glutamyltransferase; D000469:Alkaline Phosphatase; D018826:CD13 Antigens; D043384:Glutamyl Aminopeptidase; C551441:perampanel
keywords: Antiepileptic drugs; Epilepsy; Hepatic; Liver; Partial seizures; Perampanel