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A nonlinear mixed effects modelling analysis of topiramate pharmacokinetics in patients with epilepsy

Vovk, Tomaz; Jakovljević, Mihajlo B LU ; Kos, Mojca Kerec; Janković, Slobodan M; Mrhar, Ales and Grabnar, Iztok (2010) In Biological and Pharmaceutical Bulletin 33(7). p.82-1176
Abstract

Topiramate pharmacokinetics is influenced by individual factors such as patient age, renal function and co-treatment. The aim of this study was to develop a population pharmacokinetic model of topiramate to assist dosage adjustments in individual patients. Steady-state topiramate plasma concentrations in patients with epilepsy were determined by HPLC using fluorescent labelling. Demographic, biochemical data and dosing history including concomitant drug therapy were collected from patients' charts. Nonlinear mixed effects modelling was used to fit a one-compartment pharmacokinetic model. The influence of patient weight and gender, body surface area, age, creatinine clearance, serum transaminases, topiramate daily dose and co-treatment... (More)

Topiramate pharmacokinetics is influenced by individual factors such as patient age, renal function and co-treatment. The aim of this study was to develop a population pharmacokinetic model of topiramate to assist dosage adjustments in individual patients. Steady-state topiramate plasma concentrations in patients with epilepsy were determined by HPLC using fluorescent labelling. Demographic, biochemical data and dosing history including concomitant drug therapy were collected from patients' charts. Nonlinear mixed effects modelling was used to fit a one-compartment pharmacokinetic model. The influence of patient weight and gender, body surface area, age, creatinine clearance, serum transaminases, topiramate daily dose and co-treatment with carbamazepine, valproic acid, benzodiazepines, and risperidone on topiramate pharmacokinetics was evaluated. Additionally, the relationship between topiramate plasma concentration and clinical response was investigated. Volume of distribution of topiramate was 0.518 l/kg. For a typical patient oral clearance was estimated at 1.47 l/h, with interindividual variability of 39.2%. Clearance was 70% higher in patients co-treated with carbamazepine and was found to increase with patient age. Somnolence was the most frequently observed adverse event. Incidence of headache was associated with topiramate plasma concentration. Somnolence, ataxia, tremor, speech disorders and fatigue were associated with adjunctive therapy with carbamazepine, valproic acid, benzodiazepines, risperidone, and clozapine. No association of topiramate plasma concentration with frequency of seizures or patient quality of life was observed. The developed model can be used for Bayesian estimation of pharmacokinetic parameters based on sparse plasma samples and for selection of optimum dosing in routine patient care.

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author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adolescent, Adult, Anticonvulsants/adverse effects, Bayes Theorem, Child, Chromatography, High Pressure Liquid, Drug Monitoring, Epilepsy/metabolism, Female, Fructose/adverse effects, Half-Life, Humans, Male, Middle Aged, Young Adult
in
Biological and Pharmaceutical Bulletin
volume
33
issue
7
pages
7 pages
publisher
The Pharmaceutical Society of Japan
external identifiers
  • scopus:77954480747
ISSN
0918-6158
DOI
10.1248/bpb.33.1176
language
English
LU publication?
no
id
55464b34-f055-491c-9039-ad9e82ad84c9
date added to LUP
2018-09-01 23:09:43
date last changed
2019-02-20 11:25:36
@article{55464b34-f055-491c-9039-ad9e82ad84c9,
  abstract     = {<p>Topiramate pharmacokinetics is influenced by individual factors such as patient age, renal function and co-treatment. The aim of this study was to develop a population pharmacokinetic model of topiramate to assist dosage adjustments in individual patients. Steady-state topiramate plasma concentrations in patients with epilepsy were determined by HPLC using fluorescent labelling. Demographic, biochemical data and dosing history including concomitant drug therapy were collected from patients' charts. Nonlinear mixed effects modelling was used to fit a one-compartment pharmacokinetic model. The influence of patient weight and gender, body surface area, age, creatinine clearance, serum transaminases, topiramate daily dose and co-treatment with carbamazepine, valproic acid, benzodiazepines, and risperidone on topiramate pharmacokinetics was evaluated. Additionally, the relationship between topiramate plasma concentration and clinical response was investigated. Volume of distribution of topiramate was 0.518 l/kg. For a typical patient oral clearance was estimated at 1.47 l/h, with interindividual variability of 39.2%. Clearance was 70% higher in patients co-treated with carbamazepine and was found to increase with patient age. Somnolence was the most frequently observed adverse event. Incidence of headache was associated with topiramate plasma concentration. Somnolence, ataxia, tremor, speech disorders and fatigue were associated with adjunctive therapy with carbamazepine, valproic acid, benzodiazepines, risperidone, and clozapine. No association of topiramate plasma concentration with frequency of seizures or patient quality of life was observed. The developed model can be used for Bayesian estimation of pharmacokinetic parameters based on sparse plasma samples and for selection of optimum dosing in routine patient care.</p>},
  author       = {Vovk, Tomaz and Jakovljević, Mihajlo B and Kos, Mojca Kerec and Janković, Slobodan M and Mrhar, Ales and Grabnar, Iztok},
  issn         = {0918-6158},
  keyword      = {Adolescent,Adult,Anticonvulsants/adverse effects,Bayes Theorem,Child,Chromatography, High Pressure Liquid,Drug Monitoring,Epilepsy/metabolism,Female,Fructose/adverse effects,Half-Life,Humans,Male,Middle Aged,Young Adult},
  language     = {eng},
  number       = {7},
  pages        = {82--1176},
  publisher    = {The Pharmaceutical Society of Japan},
  series       = {Biological and Pharmaceutical Bulletin},
  title        = {A nonlinear mixed effects modelling analysis of topiramate pharmacokinetics in patients with epilepsy},
  url          = {http://dx.doi.org/10.1248/bpb.33.1176},
  volume       = {33},
  year         = {2010},
}