title: Pharmacodynamic and pharmacokinetic interactions of perampanel and other antiepileptic drugs in a rat amygdala kindling model.
abstract: OBJECTIVE
  This study explored the pharmacodynamic and pharmacokinetic effects of combining perampanel (PER) with commonly co-administered AEDs.
  
  
  METHODS
  A strong stimulus intensity (three-fold higher than after-discharge threshold) was used to elicit drug-resistant seizures in a rat amygdala kindling model. Vehicle, low-dose PER (0.75 mg/kg), or high-dose PER (1.5mg/kg), in combination with vehicle, levetiracetam (LEV) 50mg/kg, lamotrigine (LAM) 20mg/kg, carbamazepine (CBZ) 20mg/kg, or valproic acid (VPA) 200mg/kg, were administered intraperitoneally to groups of 6-13 rats. Seizure score, electroencephalography (EEG) seizure duration, and motor seizure duration were evaluated, with pharmacodynamic interactions determined by two-way analysis of variance (ANOVA). Motor impairment was evaluated by rotarod test and two-way ANOVA.
  
  
  RESULTS
  High-dose PER, but not low-dose PER, LEV, LAM, CBZ, or VPA, reduced EEG seizure duration, motor seizure duration, and seizure score compared with vehicle alone. However, when low-dose PER was administered in combination with LEV, LAM, CBZ, or VPA, seizure severity parameters were reduced compared with the concomitant AEDs alone. These pharmacodynamic interactions were statistically significant in some cases, but the same AED combinations were not associated with statistically significant neurotoxic interactions. Efficacy may have been slightly affected by changes in PER plasma concentrations in the presence of other AEDs:PER plasma concentrations increased with LEV or LAM co-administration, and decreased with CBZ or VPA co-administration.
  
  
  CONCLUSIONS
  Overall, these data support published Phase III data demonstrating the efficacy of PER as adjunctive therapy for the treatment of refractory partial-onset seizures in patients aged ≥ 12 years.
authors.affiliation: Global Biopharmacology, Neuroscience & General Medicine Product Creation System, Eisai Co Ltd, Tsukuba, Ibaraki, Japan. Electronic address: t2-wu@hhc.eisai.co.jp.
authors.forename: Ting
authors.initials: T
authors.lastname: Wu
authors.affiliation: Drug Metabolism and Pharmacokinetics Japan, Eisai Product Creation Systems Eisai Co Ltd, Tsukuba, Ibaraki, Japan. Electronic address: y-nagaya@hhc.eisai.co.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nagaya
authors.affiliation: Global Biopharmacology, Neuroscience & General Medicine Product Creation System, Eisai Co Ltd, Tsukuba, Ibaraki, Japan; Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan. Electronic address: t-hanada@hhc.eisai.co.jp.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Hanada
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D058256:Brain Waves / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004569:Electroencephalography; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009570:Nitriles; D011728:Pyridones / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test
chemical_list: D000927:Anticonvulsants; D009570:Nitriles; D011728:Pyridones; C551441:perampanel
keywords: Antiepileptic drugs; EEG; Kindling; Localization-related epilepsy