title: Pharmacokinetic variability of four newer antiepileptic drugs, lamotrigine, levetiracetam, oxcarbazepine, and topiramate:  a comparison of the impact of age and comedication.
abstract: BACKGROUND
  Newer antiepileptic drugs (AEDs) are widely used in patients with epilepsy. There is still insufficient documentation regarding pharmacokinetic variability of these AEDs in different patient groups.
  
  
  OBJECTIVE
  The purpose of this study was to compare age and comedication as factors contributing to pharmacokinetic variability between 4 newer AEDs (lamotrigine, levetiracetam, oxcarbazepine, and topiramate) among patients with refractory epilepsy.
  
  
  METHODS
  Data regarding age, gender, use of AEDs, daily doses, and serum concentration measurements were retrieved from a therapeutic drug monitoring database, from patients admitted to the National Center for Epilepsy, Norway, 2007-2008.
  
  
  RESULTS
  In total, 1050 patients were included, 111 younger children (2-9 years), 137 older children (10-17 years), 720 adults (18-64 years), 82 elderly (65-93 years). Fifty percent of the patients were prescribed polytherapy, in 88 different combinations. The interindividual pharmacokinetic variability was extensive, as illustrated by a 10-fold variability in serum concentration compared with dose. Age affected the apparent clearance of levetiracetam to the largest extent, as shown by a 60% increase in younger children and a 40% reduction in the elderly, respectively, compared with adults. Comedication altered the clearance of lamotrigine to the greatest extent ±70% because it is affected by both enzyme inducers and inhibitors. Hepatic enzyme inducers increased the clearance of levetiracetam and topiramate by 25% and oxcarbazepine by 75%. Valproic acid reduced the clearance of topiramate by 25%.
  
  
  CONCLUSIONS
  Age and comedication are important contributors to pharmacokinetic variability. Age had the greatest impact on levetiracetam, and comedication affected the clearance of each of the 4 AEDs investigated in this study. Pharmacokinetic drug interactions must be carefully considered when multidrug therapies are prescribed. Therapeutic drug monitoring is a valuable tool for individualizing AED therapy.
authors: Institute of Pharmacy and Biomedical Science, Faculty of Health Sciences, Oslo, Norway.
authors: Cecilie
authors: C
authors: Johannessen Landmark
authors: Arton
authors: A
authors: Baftiu
authors: Irene
authors: I
authors: Tysse
authors: Beate
authors: B
authors: Valsø
authors: Pål G
authors: PG
authors: Larsson
authors: Elisif
authors: E
authors: Rytter
authors: Svein I
authors: SI
authors: Johannessen
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination / Q000379:methods; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D000077213:Lamotrigine; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D000078330:Oxcarbazepine; D010889:Piracetam / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D000077236:Topiramate; D014227:Triazines / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D000077287:Levetiracetam; D000077213:Lamotrigine; D000078330:Oxcarbazepine; D010889:Piracetam