title: Safety and pharmacokinetic profile of rufinamide in pediatric patients aged less than 4 years with Lennox-Gastaut syndrome: An interim analysis from a multicenter, randomized, active-controlled, open-label study.
abstract: OBJECTIVE
  A good knowledge of safety and age group-specific pharmacokinetics (PK) of antiepileptic drugs (AEDs) in young pediatric patients is of great importance in clinical practice. This paper presents 6-month interim safety and PK from an ongoing 2-year open-label study (Study 303) of adjunctive rufinamide treatment in pediatric subjects ≥ 1 to < 4 years with inadequately controlled epilepsies of the Lennox-Gastaut syndrome (LGS) spectrum.
  
  
  METHODS
  Subjects (N = 37) were randomized to either rufinamide or any other approved AED chosen by the investigator as adjunctive therapy to the subject's existing regimen of 1-3 AEDs.
  
  
  RESULTS
  Interim safety results showed that treatment-emergent adverse events (TEAEs) were similar between the rufinamide (22 [88.0%]) and any-other-AED group (9 [81.8%]), with most events considered mild or moderate. A population PK analysis was conducted including plasma rufinamide concentrations from Study 303 and two other study populations of LGS subjects ≥ 4 years. The rufinamide PK profile was dose independent. The apparent clearance (CL/F) estimated from the PK model was 2.19 L/h; it was found to increase significantly as a function of body weight. Coadministration of valproic acid significantly decreased rufinamide CL/F. CL/F was not significantly affected by other concomitant AEDs, age, gender, race, hepatic function, or renal function. No adjustments to body weight-based rufinamide dosing in subjects ≥ 1 to < 4 years are necessary.
  
  
  CONCLUSIONS
  Rufinamide was safe and well tolerated in these pediatric subjects. Results from the interim analysis demonstrate that rufinamide's safety and PK profile is comparable in subjects ≥ 1 to < 4 and ≥ 4 years with LGS.
  
  
  BACKGROUND
  Study 303 (clinicaltrials.gov: NCT01405053).
authors.affiliation: Epilepsy, Sleep and Paediatric Neurophysiology Department, University Hospitals of Lyon (HCL-HFME) and Lyon Neurosciences Research Center (CRNL), 59 Bld. Pinel, 60700 Lyon, France. Electronic address: aarzimanoglou@orange.fr.
authors.forename: Alexis
authors.initials: A
authors.lastname: Arzimanoglou
authors.affiliation: Department of Pediatrics, University of South Florida, School of Medicine, Tampa, FL, USA; St. Joseph's Children's Hospital, Tampa, FL, USA; Pediatric Epilepsy and Neurology Specialists (PENS), 508 S. Habana Ave, Suite 340, Tampa, FL 33609, USA. Electronic address: jferreira@pensresearch.org.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Ferreira
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Eisai Inc., 155 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: Andrew_Satlin@eisai.com.
authors.forename: Andrew
authors.initials: A
authors.lastname: Satlin
authors.affiliation: Formerly of Eisai Inc., 100 Tice Boulevard, Woodcliff Lake, NJ, USA. Electronic address: other_medicine@yahoo.com.
authors.forename: Shannon
authors.initials: S
authors.lastname: Mendes
authors.affiliation: Eisai Medical and Scientific Affairs, Eisai Inc., 100 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: Betsy_Williams@eisai.com.
authors.forename: Betsy
authors.initials: B
authors.lastname: Williams
authors.affiliation: Eisai Ltd., Hatfield, UK. Electronic address: David_Critchley@eisai.net.
authors.forename: David
authors.initials: D
authors.lastname: Critchley
authors.affiliation: Modelling and Simulation, Clinical Pharmacology, 155 Tice Boulevard, Eisai Inc., Woodcliff Lake, NJ 07677, USA. Electronic address: Edgar_Schuck@eisai.com.
authors.forename: Edgar
authors.initials: E
authors.lastname: Schuck
authors.affiliation: Modelling and Simulation, Clinical Pharmacology, Eisai Ltd, Mosquito Way, Hatfield, Hertfordshire AL10 9SN, UK. Electronic address: Ziad_Hussein@eisai.net.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Hussein
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Eisai Inc., 155 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: Dinesh_Kumar@eisai.com.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Eisai Inc., 155 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: Shobha_Dhadda@eisai.com.
authors.forename: Shobha
authors.initials: S
authors.lastname: Dhadda
authors.affiliation: Eisai Neuroscience and General Medicine PCU, Eisai Inc., 155 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: Francesco_Bibbiani@eisai.com.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bibbiani
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D065768:Lennox Gastaut Syndrome / Q000188:drug therapy*; D008297:Male; D014230:Triazoles / Q000009:adverse effects* / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D014230:Triazoles; C079703:rufinamide
keywords: Antiepileptic drug therapy; Infants; Lennox-Gastaut syndrome; Pharmacokinetic; Randomized study; Rufinamide; safety