title: Population pharmacokinetics and dose-response relationship of levetiracetam in adult patients with epilepsy.
abstract: Levetiracetam (LEV) is commonly used as a mono- or adjunctive therapy for treating patients with partial and generalized epilepsy. This study aimed to develop a population pharmacokinetic (PK) model of LEV, based on sparse data, and to explore LEV efficacy relative to its PK properties in patients with epilepsy. We included 483 LEV concentrations from 425 patients with epilepsy that received multiple oral LEV doses. We performed a population PK analysis, implemented in NONMEM (version 7.2). In addition, we explored the relationships between seizure control and PK variables (i.e., LEV dose, trough concentration, and the number of concomitant anti-epileptic drugs). LEV concentration-time profiles were adequately described with a one-compartment, open linear model, with first-order absorption, and additive residual error. The typical population estimates of the apparent clearance (CL/F) and the volume of distribution (V/F) were 3.9L/h and 65.3L, respectively. Body weight was a significant covariate for CL/F and V/F; the estimated glomerular filtration rate only significantly affected CL/F; and concomitant intake of other anti-epileptic drugs did not significantly affect either parameter. A cumulative percentage analysis revealed that over 95% of patients that remained seizure-free received LEV doses of 2000mg/day or lower. LEV trough concentrations were not significantly different between seizure-free and seizure groups, for each LEV dose. In conclusion, we successfully developed a population PK model of LEV, which enabled investigation of LEV efficacy, relative to its PK properties. The findings in this study can be utilized to optimize LEV dosing regimens in clinical practice.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Rhee
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 Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: SeungHwan
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Neurology, Laboratory for Neurotherapeutics, Comprehensive Epilepsy Center, Biomedical Research Institute, 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, Laboratory for Neurotherapeutics, Comprehensive Epilepsy Center, Biomedical Research Institute, 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 Neurology, Laboratory for Neurotherapeutics, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Ki-Young
authors.initials: KY
authors.lastname: Jung
authors.affiliation: Department of Neurology, Laboratory for Neurotherapeutics, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; Department of Neurology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Republic of Korea.
authors.forename: Kyung-Il
authors.initials: KI
authors.lastname: Park
authors.affiliation: Department of Neurology, Laboratory for Neurotherapeutics, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Soon-Tae
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Department of Neurology, Laboratory for Neurotherapeutics, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Keun-Hwa
authors.initials: KH
authors.lastname: Jung
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
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, Laboratory for Neurotherapeutics, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea. Electronic address: stemcell.snu@gmail.com.
authors.forename: Kon
authors.initials: K
authors.lastname: Chu
authors.affiliation: Department of Neurology, Laboratory for Neurotherapeutics, Comprehensive Epilepsy Center, Biomedical Research Institute, 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; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010889:Piracetam / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012640:Seizures / Q000188:drug therapy; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam
keywords: Dose titration; Levetiracetam; Non-linear mixed effect model; Population pharmacokinetics; Seizure control