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


METHODS
Retrospective, case-matched pharmacokinetic evaluation.


METHODS
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.


CONCLUSIONS
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.
Battino
Dina
D
Carlo Besta National Neurological Institute, Milan, Italy. dbattino@istituto-besta.it
Croci
Danilo
D
Rossini
Alessandro
A
Messina
Sara
S
Mamoli
Daniela
D
Perucca
Emilio
E
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D016903:Drug Monitoring; D004790:Enzyme Induction; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D012189:Retrospective Studies; D000077236:Topiramate
D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose