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.
Similar content being viewed by others
References
Langtry HD, Gillis JC, Davis R. Topiramate: a review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of epilepsy. Drags 1997; 54(5): 752–73
Perucca E. Clinical pharmacology and therapeutic use of the new antiepileptic drugs. Fundam Clin Pharmacol 2001; 15(6): 405–17
Kamin M. Topiramate: clinical efficacy and use in nonepileptic disorders. In: Levy RH, Mattson RH, Meldrum BS, et al., editors. Antiepileptic drugs. Philadelphia (PA): Lippincott, Williams & Wilkins, 2002: 753–9
Elterman RD, Glauser TA, Wyllie E, et al. A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Topiramate YP Study Group. Neurology 1999; 52(7): 1338–44
Biton V, Montouris GD, Ritter F, et al. A randomized, placebocontrolled study of topiramate in primary generalized tonicclonic seizures. Topiramate YTC Study Group. Neurology 1999; 52(7): 1330–7
Sachdeo RC, Glauser TA, Ritter F, et al. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Topiramate YL Study Group. Neurology 1999; 52(9): 1882–7
Rosenfeld WE, Doose DR, Walker SA, et al. A study of topiramate pharmacokinetics and tolerability in children with epilepsy. Pediatr Neural 1999; 20(5): 339–44
Glauser TA, Miles MV, Tang P, et al. Topiramate pharmacokinetics in infants. Epilepsia 1999; 40(6): 788–91
May TW, Rambeck B, Jurgens U. Serum concentrations of topiramate in patients with epilepsy: influence of dose, age, and comedication. Ther Drag Monit 2002; 24(3): 366–74
Battino D, Croci D, Rossini A, et al. Serum carbamazepine concentrations in elderly patients: a case-matched pharmacokinetic evaluation based on therapeutic drug monitoring data. Epilepsia 2003 Jul; 44(7): 923–9
Berry DJ, Patsalos PN. Comparison of topiramate concentrations in plasma and serum by fluorescence polarization immunoassay. Ther Drag Monit 2000; 22(4): 460–4
Contin M, Riva R, Albani F, et al. Topiramate therapeutic monitoring in patients with epilepsy: effect of concomitant antiepileptic drugs. Ther Drug Monit 2002; 24(3): 332–7
Sachdeo RC, Sachdeo SK, Walker SA, et al. Steady-state pharmacokinetics of topiramate and carbamazepine in patients with epilepsy during monotherapy and concomitant therapy. Epilepsia 1996; 37(8): 774–80
Sachdeo RC, Sachdeo SK, Levy RH, et al. Topiramate and Phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients. Epilepsia 2002; 43(7): 691–6
Peracca E. Pharmacokinetic profile of topiramate in comparison with other new antiepileptic drags. Epilepsia 1996; 37 Suppl. 2: S8–13
Bourgeois BF. Pharmacokinetics and pharmacodynamics of topiramate. J Child Neural 2000; 15 Suppl. 1: S27–30
Perucca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drags: focus on topiramate, zonisamide and tiagabine. Clin Pharmacokinet 1996; 31(1): 29–46
Rosenfeld WE, Liao S, Kramer LD, et al. Comparison of the steady-state pharmacokinetics of topiramate and Valproate in patients with epilepsy during monotherapy and concomitant therapy. Epilepsia 1997; 38(3): 324–33
Peracca E. Is there a role for therapeutic drug monitoring of new anticonvulsants? Clin Pharmacokinet 2000; 38(3): 191–204
Twyman R, Ben-Menachem E, Veloso F. Plasma topiramate concentration versus therapeutic response during monotherapy. Epilepsia 1999; 40 Suppl.: 111–2
Reife R, Pledger G, Doose DR. Relationship of steady-state plasma topiramate concentration to clinical efficacy and tolerability [abstract]. Epilepsia 1995; 36 Suppl.: 152
Adin J, Gomez MC, Blanco Y, et al. Topiramate serum concentration-to-dose ratio: influence of age and concomitant antiepileptic drags and monitoring implications. Ther Drug Monit 2004 Jun; 26(3): 251–7
Dahlin MG, Ohman IK. Age and antiepileptic drugs influence topiramate plasma levels in children. Pediatr Neurol 2004 Oct; 31(4): 248–53
Ferrari AR, Guerrini R, Gatti G, et al. Influence of dosage, age, and co-medication on plasma topiramate concentrations in children and adults with severe epilepsy and preliminary observations on correlations with clinical response. Ther Drag Monit 2003 Dec; 25(6): 700–8
Mikaeloff Y, Rey E, Soufflet C, et al. Topiramate pharmacokinetics in children with epilepsy aged from 6 months to 4 years. Epilepsia 2004 Nov; 45(11): 1448–52
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-200544040-00005