Authors: Battino, Dina¹; Croci, Danilo¹; Rossini, Alessandro¹; Messina, Sara²; Mamoli, Daniela¹; Perucca, Emilio²

Source: Clinical Pharmacokinetics, Volume 44, Number 4, 2005 , pp. 407-416(10)

Publisher: Adis International

Abstract:

Objective: To compare the steady-state pharmacokinetics of topiramate in a large population of children and adults with epilepsy in a therapeutic drug monitoring setting.

Study design: Retrospective, case-matched pharmacokinetic evaluation.

Patients: Seventy children (aged 1–17 years) with epilepsy and 70 adult controls (aged 18–65 years) with epilepsy, matched for sex and comedication.

Methods: Topiramate apparent oral clearance (CL/F) values were calculated from steady-state serum concentrations in children and compared with those determined in controls. Comparisons were made by means of the Mann-Whitney’s U-test, or the Kruskal-Wallis test in the case of multiple comparisons. A linear regression model was used to assess potential correlation of CL/F values with age. To investigate the influence of different variables on the variability in topiramate CL/F values, a multiple regression model was developed.

Results: In the absence of enzyme-inducing comedication, mean topiramate CL/F was 42% higher in children than in adults (40.3 ± 21.0 vs 28.4 ± 15.3 mL/h/kg; p < 0.01). In children and adults comedicated with enzyme-inducing antiepileptic drugs (AEDs), topiramate CL/F values were approximately 1.5- to 2-fold higher than those observed in the absence of enzyme inducers, and the elevation in topiramate CL/F in children compared with adults was also present in the subgroups receiving enzyme inducers (66%; 76.6 ± 35.1 vs 46.1 ± 16.7 mL/h/kg; p < 0.0001). In the paediatric population, a negative correlation between CL/F and age was demonstrated, both in the absence (p < 0.01) and in the presence (p < 0.001) of enzyme induction. The independent influence of age and enzyme-inducing AEDs on topiramate CL/F was confirmed by multiple regression analysis.

Conclusion: Topiramate CL/F is highest in young children and decreases progressively with age until puberty, presumably due to age-dependent changes in the rate of drug metabolism. As a result of this, younger patients require higher dosages to achieve serum topiramate concentrations comparable with those found in older children and adults. Enzyme-inducing comedication decreases serum topiramate concentration by approximately one-half and one-third in children and adults, respectively.

Keywords: Topiramate; GABA receptor agonists; Epilepsy

Document Type: Research article

Affiliations: 1: 1 Carlo Besta National Neurological Institute, Milan, Italy 2: 2 Institute of Neurology, IRCCS C. Mondino Foundation, and Clinical Pharmacology Unit, University of Pavia, Pavia, Italy

Publication date: 2005-01-01

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