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Topiramate Pharmacokinetics in Children and Adults with Epilepsy

A Case-Matched Comparison Based on Therapeutic Drug Monitoring Data

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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.

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Acknowledgements

This study was supported by a research grant from the University of Pavia (FAR 2001-2002). The authors disclosed no potential conflicts of interest that are directly relevant to the content of this study.

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Correspondence to Dina Battino.

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Battino, D., Croci, D., Rossini, A. et al. Topiramate Pharmacokinetics in Children and Adults with Epilepsy. Clin Pharmacokinet 44, 407–416 (2005). https://doi.org/10.2165/00003088-200544040-00005

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  • DOI: https://doi.org/10.2165/00003088-200544040-00005

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