Topiramate pharmacokinetics in children and adults with epilepsy: A case-matched comparison based on therapeutic drug monitoring data

Dina Battino, Danilo Croci, Alessandro Rossini, Sara Messina, Daniela Mamoli, Emilia Perucca

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)407-416
Number of pages10
JournalClinical Pharmacokinetics
Volume44
Issue number4
DOIs
Publication statusPublished - 2005

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Drug Monitoring
Epilepsy
Pharmacokinetics
Enzymes
Anticonvulsants
Linear Models
Serum
topiramate
Enzyme Induction
Puberty
Nonparametric Statistics
Population
Retrospective Studies
Regression Analysis
Pediatrics

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Topiramate pharmacokinetics in children and adults with epilepsy : A case-matched comparison based on therapeutic drug monitoring data. / Battino, Dina; Croci, Danilo; Rossini, Alessandro; Messina, Sara; Mamoli, Daniela; Perucca, Emilia.

In: Clinical Pharmacokinetics, Vol. 44, No. 4, 2005, p. 407-416.

Research output: Contribution to journalArticle

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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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T1 - Topiramate pharmacokinetics in children and adults with epilepsy

T2 - A case-matched comparison based on therapeutic drug monitoring data

AU - Battino, Dina

AU - Croci, Danilo

AU - Rossini, Alessandro

AU - Messina, Sara

AU - Mamoli, Daniela

AU - Perucca, Emilia

PY - 2005

Y1 - 2005

N2 - 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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