title: Population Pharmacokinetic Modeling of Levetiracetam in Pediatric and Adult Patients With Epilepsy by Using Routinely Monitored Data.
abstract: Levetiracetam, a second-generation antiepileptic drug, is frequently used for managing partial-onset seizures. About 70% of the administered dose is excreted in urine unchanged, and dosage adjustment is recommended based on the individual's renal function. In this study, a population pharmacokinetic model of levetiracetam was developed using routinely monitored serum concentration data for individualized levetiracetam therapy.
  
  
  
  Patients whose serum concentrations of levetiracetam at steady-state were routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were enrolled. The influence of patient characteristics on levetiracetam pharmacokinetics was evaluated using the nonlinear mixed-effects modeling (NONMEM) program.
  
  
  
  A total of 583 steady-state concentrations from 225 patients were used for the analysis. The median patient age and estimated glomerular filtration rate (eGFR) were 38 (range: 1-89) years and 98 (15-189) mL·min·1.73 m, respectively. Serum concentration-time data of levetiracetam were well described by a 1-compartment model with first-order absorption. Oral clearance was allometrically related to the individual body weight and eGFR. An increase in the dose significantly increased oral clearance. No improvement in model fit was observed by including the covariate of any concomitant antiepileptic drugs. The population mean clearance for an adult weighing 70 kg and with a normal renal function was 4.8 and 5.9 L/h for 500 mg bis in die (bid) and 1500 mg bid, respectively.
  
  
  
  Oral clearance allometrically related with body weight and eGFR can well predict the routine therapeutic drug monitoring data from pediatric to aged patients with varying renal function. Dosage adjustments based on renal function are effective in controlling the trough and peak concentrations in similar ranges.
authors.affiliation: *Department of Clinical Pharmacy and Education, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; †Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan; and ‡Department of Epilepsy, Movement Disorders and Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Ito
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yano
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Hashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuda
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Sugimoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yonezawa
authors.forename: Akio
authors.initials: A
authors.lastname: Ikeda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Matsubara
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007223:Infant; D007677:Kidney Function Tests; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010889:Piracetam / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D012189:Retrospective Studies; D012640:Seizures / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam