title: Population Pharmacokinetics of Topiramate in Japanese Pediatric and Adult Patients With Epilepsy Using Routinely Monitored Data.
abstract: Topiramate is a second-generation antiepileptic drug used as monotherapy and adjunctive therapy in adults and children with partial seizures. A population pharmacokinetic (PPK) analysis was performed to improve the topiramate dosage adjustment for individualized treatment.
  
  
  
  Patients whose steady-state serum concentration of topiramate was routinely monitored at Kyoto University Hospital from April 2012 to March 2013 were included in the model-building data. A nonlinear mixed effects modeling program was used to evaluate the influence of covariates on topiramate pharmacokinetics. The obtained PPK model was evaluated by internal model validations, including goodness-of-fit plots and prediction-corrected visual predictive checks, and was externally confirmed using the validation data from January 2015 to December 2015.
  
  
  
  A total of 177 steady-state serum concentrations from 93 patients were used for the model-building analysis. The patients' age ranged from 2 to 68 years, and body weight ranged from 8.6 to 105 kg. The median serum concentration of topiramate was 1.7 mcg/mL, and half of the patients received carbamazepine coadministration. Based on a one-compartment model with first order absorption and elimination, the apparent volume of distribution was 105 L/70 kg, and the apparent clearance was allometrically related to the body weight as 2.25 L·h·70 kg without carbamazepine or phenytoin. Combination treatment with carbamazepine or phenytoin increased the apparent clearance to 3.51 L·h·70 kg. Goodness-of-fit plots, prediction-corrected visual predictive check, and external validation using the validation data from 43 patients confirmed an appropriateness of the final model. Simulations based on the final model showed that dosage adjustments allometrically scaling to body weight can equalize the serum concentrations in children of various ages and adults.
  
  
  
  The PPK model, using the power scaling of body weight, effectively elucidated the topiramate serum concentration profile ranging from pediatric to adult patients. Dosage adjustments based on body weight and concomitant antiepileptic drug help obtain the dosage of topiramate necessary to reach an effective concentration in each individual.
authors.affiliation: *Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan; †Department of Clinical Pharmacy and Education, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; ‡Department of Pharmacy, Kobe University Hospital, Kobe; and §Department of Epilepsy, Movement Disorders and Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Ikuko
authors.initials: I
authors.lastname: Yano
authors.forename: Satoko
authors.initials: S
authors.lastname: Ito
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Sugimoto
authors.forename: Shota
authors.initials: S
authors.lastname: Yamamoto
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; D000368:Aged; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D044466:Asian People; D001835:Body Weight / Q000187:drug effects; D002220:Carbamazepine / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring / Q000379:methods; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D008991:Monitoring, Physiologic / Q000379:methods; D010672:Phenytoin / Q000493:pharmacokinetics / Q000627:therapeutic use; D012640:Seizures / Q000188:drug therapy; D000077236:Topiramate; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D010672:Phenytoin