title: Factors influencing topiramate clearance in adult patients with epilepsy: A population pharmacokinetic analysis.
abstract: OBJECTIVE
  To identify the factors influencing topiramate pharmacokinetics (PK) in a large population of adult patients with epilepsy using population PK analysis.
  
  
  METHODS
  Clinical data and blood samples were collected from 550 adult patients with epilepsy treated using topiramate. Nonlinear mixed effects modeling software (NONMEM, version 7.2) was used to fit the plasma concentration to a one-compartment PK model. Demographic and clinical variables tested as potential covariates were age, sex, body weight, height, serum creatinine, creatinine clearance (CLcr), total bilirubin, prothrombin time, albumin, aspartate transaminase (AST), alanine transaminase (ALT), daily dose (DOSE), and concomitant medications (phenytoin [PHT], clobazam, carbamazepine [CBZ], valproic acid, lamotrigine, levetiracetam, oxcarbazepine [OXC], pregabalin, clonazepam, and phenobarbital [PB]).
  
  
  RESULTS
  The final PK model was CL/F (L/h)=(1.16+1.36 × PHT+1.01 × CBZ+0.643 × OXC+0.476 × PB)×(CLcr/90)(0.310)×(DOSE/100)(0.0929) (1 in patients co-medicated with each drug, 0 in otherwise) and V/F (L)=109 × (WT/62). For a typical patient with CLcr of 90 mL/min and DOSE of 100mg, co-medication with PHT, CBZ, OXC, and PB increased the CL/F to 2.52 (1.16+1.36)L/h, 2.17 (1.16+1.01)L/h, 1.803 (1.16+0.643)L/h, and 1.636 (1.16+0.476)L/h, respectively, which was 117, 87, 55, and 41% higher, respectively, than in patients without co-medication.
  
  
  CONCLUSIONS
  The apparent clearance of topiramate increased with co-medication of PHT, CBZ, OXC, and PB. This population PK model can be applied for optimizing topiramate dosage regimens in actual clinical practice.
authors.affiliation: Department of Neurology, Inha University Hospital, Incheon, Republic of Korea.
authors.forename: Eun-Kee
authors.initials: EK
authors.lastname: Bae
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Jongtae
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
authors.forename: Jung-Won
authors.initials: JW
authors.lastname: Shin
authors.affiliation: Department of Neurology, Comprehensive Epilepsy Center, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Jangsup
authors.initials: J
authors.lastname: Moon
authors.affiliation: Department of Neurology, Comprehensive Epilepsy Center, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Keon-Joo
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Department of Neurology, Comprehensive Epilepsy Center, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Yong-Won
authors.initials: YW
authors.lastname: Shin
authors.affiliation: Department of Neurology, Comprehensive Epilepsy Center, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Kim
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Dongseong
authors.initials: D
authors.lastname: Shin
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.affiliation: Department of Neurology, Comprehensive Epilepsy Center, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea. Electronic address: sangkun2923@gmail.com.
authors.forename: Sang Kun
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002220:Carbamazepine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; 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; D000078330:Oxcarbazepine; D010634:Phenobarbital / Q000627:therapeutic use; D010672:Phenytoin / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077236:Topiramate; D014635:Valproic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D014635:Valproic Acid; D010672:Phenytoin; D000078330:Oxcarbazepine; D010634:Phenobarbital
keywords: Epilepsy; NONMEM; Population pharmacokinetics; Topiramate