Skip to main content

Advertisement

Springer Nature Link
Log in

Pharmacokinetics and Drug Interaction of Antiepileptic Drugs in Children and Adolescents

  • Review Article
  • Published:
Pediatric Drugs Aims and scope Submit manuscript

Abstract

Selecting the most appropriate antiepileptic drug (AED) or combination of drugs for each patient and identifying the most suitable therapeutic regimen for their needs is increasingly challenging, especially among pediatric populations. In fact, the pharmacokinetics of several drugs vary widely in children with epilepsy because of age-related factors, which can influence the absorption, distribution, metabolism, and elimination of the pharmacological agent. In addition, individual factors, such as seizure type, associated comorbidities, individual pharmacokinetics, and potential drug interactions, may contribute to large fluctuations in serum drug concentrations and, therefore, clinical response. Therapeutic drug concentration monitoring (TDM) is an essential tool to deal with this complexity, enabling the definition of individual therapeutic concentrations and adaptive control of dosing to minimize drug interactions and prevent loss of efficacy or toxicity. Moreover, pharmacokinetic/pharmacodynamic modelling integrated with dashboard systems have recently been tested in antiepileptic therapy, although more clinical trials are required to support their use in clinical practice. We review the mechanism of action, pharmacokinetics, drug–drug interactions, and safety/tolerability profiles of the main AEDs currently used in children and adolescents, paying particular regard to issues of relevance when treating this patient population. Indications for TDM are provided for each AED as useful support to the clinical management of pediatric patients with epilepsy by optimizing pharmacological therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Guerrini R. Epilepsy in children. Lancet. 2006;367(9509):499–524.

    Article  PubMed  Google Scholar 

  2. Brodie MJ, Barry SJ, Bamagous GA, et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology. 2012;78:1548–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Perucca P, Scheffer IE, Kiley M. The management of epilepsy in children and adults. Med J Aust. 2018;208(5):226–33.

    Article  PubMed  Google Scholar 

  4. Italiano D, Perucca E. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age: an update. Clin Pharmacokinet. 2013;52(8):627–45.

    Article  CAS  PubMed  Google Scholar 

  5. Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs–best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008;49(7):1239–76.

    Article  CAS  PubMed  Google Scholar 

  6. Zaccara G, Perucca E. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs. Epileptic Disord. 2014;16(4):409–31.

    PubMed  Google Scholar 

  7. Perucca E. Clinically relevant drug interactions with antiepileptic drugs. Br J Clin Pharmacol. 2006;61(3):246–55.

    Article  CAS  PubMed  Google Scholar 

  8. Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol. 2003;2(6):347–56.

    Article  CAS  PubMed  Google Scholar 

  9. Perucca E. The pharmacology of new antiepileptic drugs: Does a novel mechanism of action really matter? CNS Drugs. 2011;25:07–12.

    Article  Google Scholar 

  10. Mula M. Epilepsy and psychiatric comorbidities: drug selection. Curr Treat Options Neurol. 2017;19(12):44.

    Article  PubMed  Google Scholar 

  11. Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551–63.

    Article  CAS  PubMed  Google Scholar 

  12. Tolou-Ghamari Z, Zare M, Habibabadi JM, Najafi MR. A quick review of carbamazepine pharmacokinetics in epilepsy from 1953 to 2012. J Res Med Sci. 2013;18(1):S81–5.

    PubMed  PubMed Central  Google Scholar 

  13. Brodie MJ, Mintzer S, Pack AM, et al. Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia. 2013;54:11–27.

    Article  CAS  PubMed  Google Scholar 

  14. Djordjevic N, Jankovic SM, Milovanovic JR. Pharmacokinetics and pharmacogenetics of carbamazepine in children. Eur J Drug Metab Pharmacokinet. 2017;42(5):729–44.

    Article  CAS  PubMed  Google Scholar 

  15. Riva R, Contin M, Albani F, et al. Free and total serum concentrations of carbamazepine and carbamazepine-10,11-epoxide in infancy and childhood. Epilepsia. 1985;26(4):320–2.

    Article  CAS  PubMed  Google Scholar 

  16. Battino D, Estienne M, Avanzini G. Clinical pharmacokinetics of antiepileptic drugs in paediatric patients. Part II. Phenytoin, carbamazepine, sulthiame, lamotrigine, vigabatrin, oxcarbazepine and felbamate. Clin Pharmacokinet. 1995;29(5):341–69.

    Article  CAS  PubMed  Google Scholar 

  17. Patsalos PN, Perucca E. Clinically important drug interactions in epilpesy: interaction between antiepileptic drugs and other drugs. Lancet Neurol. 2003;2(8):473–81.

    Article  CAS  PubMed  Google Scholar 

  18. Brodie MJ, Mumford JP, 012 Study Group. Double-blind substitution of vigabatrin and valproate in carbamazepine-resistant partial epilepsy. Epilepsy Res. 1999;34:199–205.

    Article  CAS  PubMed  Google Scholar 

  19. Besag FM, Berry DJ, Pool F, et al. Carbamazepine toxicity with lamotrigine: pharmacokinetic or pharmacodynamic interaction? Epilepsia. 1998;39:183–7.

    Article  CAS  PubMed  Google Scholar 

  20. Patsalos PN, Berry DJ. Therapeutic drug monitoring of antiepileptic drugs by use of saliva. Ther Drug Monit. 2013;35(1):4–29.

    Article  CAS  PubMed  Google Scholar 

  21. Pellock JM. Carbamazepine side effects in children and adults. Epilepsia. 1987;28(3):S64–70.

    Article  PubMed  Google Scholar 

  22. Kafadar İ, Kılıç BA, Arapoglu M, et al. Evaluation of thyroid hormones in children receiving carbamazepine or valproate: a prospective study. J Child Neurol. 2015;30(1):63–8.

    Article  PubMed  Google Scholar 

  23. Pelizza L, De Luca P, La Pesa M, Minervino A. Drug-induced systemic lupus erythematosus after 7 years of treatment with carbamazepine. Acta Biomed. 2006;77:17–9.

    PubMed  Google Scholar 

  24. Grover S, Kukreti R. HLA alleles and hypersensitivity to carbamazepine: an updated systematic review with meta-analysis. Pharmacogenet Genom. 2014;24(2):94–112.

    Article  CAS  Google Scholar 

  25. Van Wieringen A, Vrijlandt CM. Ethosuximide intoxication caused by interaction with isoniazid. Neurology. 1983;33:1227–8.

    Article  PubMed  Google Scholar 

  26. Buchanan RA, Fernandez L, Kinkel AW. Absorption and elimination of ethosuximide in children. J Clin Pharmacol J New Drugs. 1969;9(6):393–8.

    CAS  PubMed  Google Scholar 

  27. Battino D, Estienne M, Avanzini G. Clinical pharmacokinetics of antiepileptic drugs in paediatric patients. Part I: phenobarbital, primidone, valproic acid, ethosuximide and mesuximide. Clin Pharmacokinet. 1995;29(4):257–86.

    Article  CAS  PubMed  Google Scholar 

  28. Rowan AJ, Meijer JW, de Beer-Pawlikowski N, et al. Valproate-ethosuximide combination therapy for refractory absence seizures. Arch Neurol. 1983;40:797–802.

    Article  CAS  PubMed  Google Scholar 

  29. Wallace SJ. A comparative review of the adverse effects of anticonvulsants in children with epilepsy. Drug Saf. 1996;15(6):378–93.

    Article  CAS  PubMed  Google Scholar 

  30. Posner EB, Mohamed K, Marson AG. A systematic review of treatment of typical absence seizures in children and adolescents with ethosuximide, sodium valproate or lamotrigine. Seizure. 2005;14:117–22.

    Article  PubMed  Google Scholar 

  31. Newton CR, Garcia HH. Epilepsy in poor regions of the world. Lancet. 2012;380(9848):1193–201.

    Article  PubMed  Google Scholar 

  32. Czapiński P, Blaszczyk B, Czuczwar SJ. Mechanisms of action of antiepileptic drugs. Curr Top Med Chem. 2005;5(1):3–14.

    Article  PubMed  Google Scholar 

  33. Pacifici GM. Clinical pharmacology of phenobarbital in neonates: effects, metabolism and pharmacokinetics. Curr Pediatr Rev. 2016;12(1):48–54.

    Article  CAS  PubMed  Google Scholar 

  34. Filippi L, la Marca G, Cavallaro G, et al. Phenobarbital for neonatal seizures in hypoxic ischemic encephalopathy: a pharmacokinetic study during whole body hypothermia. Epilepsia. 2011;52(4):794–801.

    Article  CAS  PubMed  Google Scholar 

  35. Grasela TH Jr, Donn SM. Neonatal population pharmacokinetics of phenobarbital derived from routine clinical data. Dev Pharmacol Ther. 1985;8(6):374–83.

    Article  PubMed  Google Scholar 

  36. Yukawa M, Yukawa E, Suematsu F, et al. Population pharmacokinetics of phenobarbital by mixed effect modelling using routine clinical pharmacokinetic data in Japanese neonates and infants: an update. J Clin Pharm Ther. 2011;36(6):704–10.

    Article  CAS  PubMed  Google Scholar 

  37. Neonatal Formulary. 6th ed. Wiley, Limited European Distribution Centre New Era Estate, Oldlands Way Bognor Regis, West Sussex, PO22 9NQ, UK. 2011; pp 400–402.

  38. Manuyakorn W, Siripool K, Kamchaisatian W, et al. Phenobarbital- induced severe cutaneous adverse drug reactions are associated with CYP2C19*2 in Thai children. Pediatr Allergy Immunol. 2013;24(3):299–303.

    Article  PubMed  Google Scholar 

  39. Kwan P, Brodie MJ. Phenobarbital for the treatment of epilepsy in the 21st century: a critical review. Epilepsia. 2004;45(9):1141–9.

    Article  CAS  PubMed  Google Scholar 

  40. Eadie MJ. Phenytoin. In: Shorvon S, Perucca E, Engel J, editors. The treatment of epilepsy. 3rd ed. New York: Wiley-Blackwell; 2009. pp. 605–18.

    Book  Google Scholar 

  41. Franco V, Perucca E. CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effects. Expert Opin Drug Metab Toxicol. 2015;11(8):1269–79.

    Article  CAS  PubMed  Google Scholar 

  42. Luef G, Chemelli A, Birbamer G, et al. Phenytoin overdosage and cerebellar atrophy in epileptic patients: clinical and MRI findings. Eur Neurol. 1994;34(s1):79–81.

    Article  PubMed  Google Scholar 

  43. O’Brien TJ, Cascino GD, So EL, Hanna DR. Incidence and clinical consequences of the purple glove syndrome in patients receiving intravenous phenytoin. Neurology. 1998;51:1034–9.

    Article  PubMed  Google Scholar 

  44. Corrêa JD, Queiroz-Junior CM, Costa JE, et al. Phenytoin-induced gingival overgrowth: a review of the molecular, immune, and inflammatory features. ISRN Dent. 2011;2011:497850.

    PubMed  PubMed Central  Google Scholar 

  45. Gorman KM, Shahwan A. Sultiame revisited: treatment of refractory absence seizures. Epileptic Disord. 2016;18(3):329–33.

    PubMed  Google Scholar 

  46. Leniger T, Wiemann M, Bingmann D, et al. Carbonic anhydrase inhibitor sulthiame reduces intracellular pH and epileptiform activity of hippocampal CA3 neurons. Epilepsia. 2002;43(5):469–74.

    Article  CAS  PubMed  Google Scholar 

  47. May TW, Korn-Merker E, Rambeck B, Boenigk HE. Pharmacokinetics of sulthiame in epileptic patients. Ther Drug Monit. 1994;16(3):251–7.

    Article  CAS  PubMed  Google Scholar 

  48. Pichini S, Papaseit E, Joya X, et al. Pharmacokinetics and therapeutic drug monitoring of psychotropic drugs in pediatrics. Ther Drug Monit. 2009;31(3):283–318.

    Article  CAS  PubMed  Google Scholar 

  49. Yamamoto Y, Takahashi Y, Imai K, et al. Interaction between sulthiame and clobazam: sulthiame inhibits the metabolism of clobazam, possibly via an action on CYP2C19. Epilepsy Behav. 2014;34:124–6.

    Article  PubMed  Google Scholar 

  50. Reimers A, Berg JA, Burns ML, et al. Reference ranges for antiepileptic drugs revisited: a practical approach to establish national guidelines. Drug Des Devel Ther. 2018;12:271–80.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Milburn-McNulty P, Powell G, Sills GJ, Marson AG. Sulthiame monotherapy for epilepsy. Cochrane Database Syst Rev.2014;(3):CD010062.

  52. Borggraefe I, Bonfert M, Bast T, et al. Levetiracetam vs. sulthiame in benign epilepsy with centrotemporal spikes in childhood: a double-blinded, randomized, controlled trial (German HEAD Study). Eur J Paediatr Neurol. 2013;17(5):507–14.

    Article  PubMed  Google Scholar 

  53. Tomson T, Battino D, Perucca E. Valproic acid after five decades of use in epilepsy: time to reconsider the indications of a time-honoured drug. Lancet Neurol. 2016;15:210–8.

    Article  CAS  PubMed  Google Scholar 

  54. Perucca E. Pharmacological and therapeutic properties of valproate. A summary after 35 years of clinical experience. CNS Drugs. 2002;16(10):695–714.

    Article  CAS  PubMed  Google Scholar 

  55. Chateauvieux S, Morceau F, Dicato M, Diederich M. Molecular and therapeutic potential and toxicity of valproic Acid. J. Biomed. Biotechnol. 2010.

  56. Pisani F, Oteri G, Russo MF, et al. The efficacy of valproate–lamotrigine comedication in refractory complex partial seizures: evidence for a pharmacodynamic interaction. Epilepsia. 1999;40:1141–6.

    Article  CAS  PubMed  Google Scholar 

  57. Anderson M, Choonara I. A systematic review of safety monitoring and drug toxicity in published randomised controlled trials of antiepileptic drugs in children over a 10-year period. Arch Dis Child. 2010;95(9):731–8.

    Article  PubMed  Google Scholar 

  58. Gerstner T, Teich M, Bell N, et al. Valproate-associated coagulopathies are frequent and variable in children. Epilepsia. 2006;47(7):1136–43.

    Article  PubMed  Google Scholar 

  59. Gopaul S, Farrell K, Abbott F. Effects of age and polytherapy, risk factors of valproic acid (VPA) hepatotoxicity, on the excretion of thiol conjugates of (E)-2,4-diene VPA in people with epilepsy taking VPA. Epilepsia. 2003;44(3):322–8.

    Article  CAS  PubMed  Google Scholar 

  60. European Medicines Agency. Assessment report. Procedure under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Valproate_and_related_substances_31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500177352.pdf. Accessed 4 Dec 2017.

  61. Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent teratogenicity of valproate in mono- and polytherapy: an observational study. Neurology. 2015;85(10):866–72.

    Article  CAS  PubMed  Google Scholar 

  62. Johannessen Landmark C, Farmen AH, Burns ML, et al. Pharmacokinetic variability of valproate during pregnancy—implications for the use of therapeutic drug monitoring. Epilepsy Res. 2018;141:31–7.

    Article  CAS  PubMed  Google Scholar 

  63. Pellock JM, Faught E, Leppik IE, et al. Felbamate: consensus of current clinical experience. Epilepsy Res. 2006;71(2–3):89–101.

    Article  PubMed  Google Scholar 

  64. Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox–Gastaut syndrome). N Engl J Med. 1993;328(1):29–33.

    Article  Google Scholar 

  65. Leppik IE, White JR. Felbamate. In: Shorvon S, Perucca E, Engel J, editors. The treatment of epilepsy. 3rd ed. New York: Wiley-Blackwell; 2009. pp. 511–8.

    Book  Google Scholar 

  66. Banfield CR, Zhu GR, Jen JF, et al. The effect of age on the apparent clearance of felbamate: a retrospective analysis using nonlinear mixed-effects modeling. Ther Drug Monit. 1996;18(1):19–29.

    Article  CAS  PubMed  Google Scholar 

  67. Kelley MT, Walson PD, Cox S, Dusci LJ. Population pharmacokinetics of felbamate in children. Ther Drug Monit. 1997;19(1):29–36.

    Article  CAS  PubMed  Google Scholar 

  68. Carmant L, Holmes GL, Sawyer S, et al. Efficacy of felbamate in therapy for partial epilepsy in children. J Pediatr. 1994;125(3):481–6.

    Article  CAS  PubMed  Google Scholar 

  69. Perucca E. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age. Clin Pharmacokinet. 2006;45(4):351–63.

    Article  CAS  PubMed  Google Scholar 

  70. Pellock JM. Felbamate. Epilepsia. 1999;40(Suppl 5):S57–62.

    Article  CAS  PubMed  Google Scholar 

  71. Chen C, Casale EJ, Duncan B, et al. Pharmacokinetics of lamotrigine in children in the absence of other antiepileptic drugs. Pharmacotherapy. 1999;19(4):437–41.

    Article  PubMed  Google Scholar 

  72. Johannessen Landmark C, Baftiu A, Tysse I, et al. Pharmacokinetic variability of four newer antiepileptic drugs, lamotrigine, levetiracetam, oxcarbazepine, and topiramate: a comparison of the impact of age and comedication. Ther Drug Monit. 2012;34(4):440–5.

    CAS  PubMed  Google Scholar 

  73. Battino D, Croci D, Granata T, et al. Single-dose pharmacokinetics of lamotrigine in children: influence of age and antiepileptic comedication. Ther Drug Monit. 2001;23(3):217–22.

    Article  CAS  PubMed  Google Scholar 

  74. Theis JG, Sidhu J, Palmer J, et al. Lack of pharmacokinetic interaction between oxcarbazepine and lamotrigine. Neuropsychopharmacology. 2005;30(12):2269–74.

    Article  CAS  PubMed  Google Scholar 

  75. Landmark CJ, Johannessen SI, Tomson T. Dosing strategies for antiepileptic drugs: from a standard dose for all to individualised treatment by implementation of therapeutic drug monitoring. Epileptic Disord. 2016;18(4):367–83.

    PubMed  Google Scholar 

  76. Egunsola O, Choonara I, Sammons HM. Safety of lamotrigine in paediatrics: a systematic review. BMJ Open. 2015;5(6):e007711.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Hirsch LJ, Weintraub DB, Buchsbaum R, et al. Predictors of Lamotrigine-associated Rash. Epilepsia. 2006;47(2):318–22.

    Article  CAS  PubMed  Google Scholar 

  78. Deshpande LS, Delorenzo RJ. Mechanism of levetiracetam in the control of status epilepticus and epilepsy. Front Neurol. 2014;5:11.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Weijenberg A, Brouwer OF, Callenbach PM. Levetiracetam monotherapy in children with epilepsy: a systematic review. CNS Drugs. 2015;29(5):371–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Walker MC, Patsalos PN. Clinical pharmacokinetics of new antiepileptic drugs. Pharmacol Ther. 1995;67(3):351–84.

    Article  CAS  PubMed  Google Scholar 

  81. Pellock JM, Glauser TA, Bebin EM, et al. Pharmacokinetic study of levetiracetam in children. Epilepsia. 2001;42(12):1574–9.

    Article  CAS  PubMed  Google Scholar 

  82. Toublanc N, Sargentini-Maier ML, Lacroix B, et al. Retrospective population pharmacokinetic analysis of levetiracetam in children and adolescents with epilepsy. Clin Pharmacokinet. 2008;47(5):333–41.

    Article  CAS  PubMed  Google Scholar 

  83. Shoaf TL, Lu Z, Yee KF, Gauer LJ. Evaluation of the relative risk of psychiatric and behavioral adverse events in pediatric patients with refractory partial seizures treated with levetiracetam—impact of prior history and a comparison with adult data. Epilepsia. 2005;46(s8):204–5.

    Google Scholar 

  84. Verrotti A, D’Adamo E, Parisi P, et al. Levetiracetam in childhood epilepsy. Paediatr Drugs. 2010;12(3):177–86.

    Article  PubMed  Google Scholar 

  85. Schmidt D, Elger CE. What is the evidence that oxcarbazepine and carbamazepine are distinctly different antiepileptic drugs? Epilepsy Behav. 2004;5(5):627–35.

    Article  PubMed  Google Scholar 

  86. Dickinson RG, Hooper WD, Dunstan PR, Eadie MJ. First dose and steady-state pharmacokinetics of oxcarbazepine and its 10-hydroxy metabolite. Eur J Clin Pharmacol. 1989;37(1):69–74.

    CAS  PubMed  Google Scholar 

  87. Bülau P, Paar WD, von Unruh GE. Pharmacokinetics of oxcarbazepine and 10-hydroxy-carbazepine in the newborn child of an oxcarbazepine-treated mother. Eur J Clin Pharmacol. 1988;34(3):311–3.

    Article  PubMed  Google Scholar 

  88. Perucca E. The clinical pharmacokinetics of the new antiepileptic drugs. Epilepsia. 1999;40(9):S7–13.

    Article  CAS  PubMed  Google Scholar 

  89. Beran RG. Cross-reactive skin eruption with both carbamazepine and oxcarbazepine. Epilepsia. 1993;34(1):163–5.

    Article  CAS  PubMed  Google Scholar 

  90. Donati F, Gobbi G, Oxcarbazepine Cognitive Study Group. The cognitive effects of oxcarbazepine versus carbamazepine or valproate in newly diagnosed children with partial seizures. Seizure. 2007;16(8):670–9.

    Article  PubMed  Google Scholar 

  91. Rey E, Bulteau C, Motte J, et al. Oxcarbazepine pharmacokinetics and tolerability in children with inadequately controlled epilepsy. J Clin Pharmacol. 2004;44(11):1290–300.

    Article  CAS  PubMed  Google Scholar 

  92. Garoufi A, Vartzelis A. Weight gain in children on oxcarbazepine monotherapy. Epilepsy Res. 2016;122:110–3.

    Article  CAS  PubMed  Google Scholar 

  93. Sachdeo RC, Wasserstein A, Mesenbrick PJ, D’Scouza J. Effects of oxcarbazepine on sodium concentration and water handling. Ann Neurol. 2002;51(5):613–20.

    Article  CAS  PubMed  Google Scholar 

  94. Abtahi MA, Abtahi SH, Fazel F, et al. Topiramate and the vision: a systematic review. Clin Ophthalmol. 2012;6:117–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Easterling DE, Zakszewski T, Moyer MD, et al. Plasma pharmacokinetics of topiramate, a new anticonvulsant in humans. Epilepsia. 1988;29:662.

    Google Scholar 

  96. Garnett WR. Clinical pharmacology of topiramate: a review. Epilepsia. 2000;41(s1):61–5.

    Article  Google Scholar 

  97. Froscher W, Schier KR, Hoffmann M, et al. Topiramate: a prospective study on the relationship between concentration, dosage and adverse events in epileptic patients on combination therapy. Epileptic Disord. 2005;7(3):237–48.

    PubMed  Google Scholar 

  98. Jacob S, Nair AB. An updated overview on therapeutic drug monitoring of recent antiepileptic drugs. Drugs R D. 2016;16(4):303–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Levisohn PM. Safety and tolerability of topiramate in children. J Child Neurol. 2000;15(s1):S22–6.

    Article  PubMed  Google Scholar 

  100. Wisniewski M, Lukasik-Glebocka M, Anand JS. Acute topiramate overdose—clinical manifestations. Clin Toxicol (Phila). 2009;47(4):317–20.

    Article  CAS  PubMed  Google Scholar 

  101. Rapoport Y, Benegas N, Kuchtey RW, Joos KM. Acute myopia and angle closure glaucoma from topiramate in a seven-year-old: a case report and review of the literature. BMC Pediatr. 2014;14:96.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Bootsma HP, Coolen F, Aldenkamp AP, et al. Topiramate in clinical practice: long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center. Epilepsy Behav. 2004;5:380–7.

    Article  CAS  PubMed  Google Scholar 

  103. Haegele KD, Schechter PJ. Kinetics of the enantiomers of vigabatrin after an oral dose of the racemate or the inactive S-enantiomer. Clin Pharmacol Ther. 1986;40:581–6.

    Article  CAS  PubMed  Google Scholar 

  104. Mudigoudar B, Weatherspoon S, Wheless JW. Emerging antiepileptic drugs for severe pediatric epilepsies. Semin Pediatr Neurol. 2016;23(2):167–79.

    Article  PubMed  Google Scholar 

  105. Kramer G, Wohlrab G. Vigabatrin. In: Shorvon S, Perucca E, Engel J, editors. The treatment of epilepsy. 3rd ed. New York: Wiley-Blackwell; 2009. pp. 699–712.

    Book  Google Scholar 

  106. Jackson MC, Jafarpour S, Klehm J, et al. Effect of vigabatrin on seizure control and safety profile in different subgroups of children with epilepsy. Epilepsia. 2017;58(9):1575–85.

    Article  CAS  PubMed  Google Scholar 

  107. Hussain SA, Tsao J, Li M, et al. Risk of vigabatrin-associated brain abnormalities on MRI in the treatment of infantile spasms is dose-dependent. Epilepsia. 2017;58(4):674–82.

    Article  CAS  PubMed  Google Scholar 

  108. Sills G, Brodie M. Pharmacokinetics and drug interactions with zonisamide. Epilepsia. 2007;48(3):435–41.

    Article  CAS  PubMed  Google Scholar 

  109. Cross JH, Auvin S, Patten A, Giorgi L. Safety and tolerability of zonisamide in paediatric patients with epilepsy. Eur J Paediatr Neurol. 2014;18(6):747–58.

    Article  PubMed  Google Scholar 

  110. Glauser TA, Pellock JM. Zonisamide in pediatric epilepsy: review of the Japanese experience. J Child Neurol. 2002;17(2):87–96.

    Article  PubMed  Google Scholar 

  111. Johannessen Landmark C, Patsalos PN. Drug interactions involving the new second- and third-generation antiepileptic drugs. Expert Rev Neurother. 2010;10(1):119–40.

    Article  CAS  PubMed  Google Scholar 

  112. Yang X, Bognar J Jr, He T, et al. Brivaracetam augments short-term depression and slows vesicle recycling. Epilepsia. 2015;56(12):1899–909.

    Article  CAS  PubMed  Google Scholar 

  113. Schoemaker R, Wade JR, Stockis A. Extrapolation of a brivaracetam exposure-response model from adults to children with focal seizures. Clin Pharmacokinet. 2018;57(7):843–54.

    Article  CAS  PubMed  Google Scholar 

  114. Krasowski MD. Therapeutic drug monitoring of the newer anti-epilepsy medications. Pharmaceuticals (Basel). 2010;3(6):1909–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Stockis A, Sargentini-Maier ML, Horsmans Y. Brivaracetam disposition in mild to severe hepatic impairment. J Clin Pharmacol. 2013;53(6):633–41.

    Article  CAS  PubMed  Google Scholar 

  116. Schoemaker R, Wade JR, Stockis A. Brivaracetam population pharmacokinetics in children with epilepsy aged 1 month to 16 years. Eur J Clin Pharmacol. 2017;73(6):727–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Stephen LJ, Brodie MJ. Brivaracetam: a novel antiepileptic drug for focal-onset seizures. Ther Adv Neurol Disord. 2017;11:1–10.

    Google Scholar 

  118. Stockis A, Watanabe S, Scheen AJ, et al. Effect of rifampin on the disposition of brivaracetam in human subjects: further insights into brivaracetam hydrolysis. Drug Metab Dispos. 2016;44(6):792–9.

    Article  CAS  PubMed  Google Scholar 

  119. Stockis A, Rolan P. Effect of brivaracetam (400 mg/day) on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive in healthy women. J Clin Pharmacol. 2013;53(12):1313–21.

    Article  CAS  PubMed  Google Scholar 

  120. Coppola G, Iapadre G, Operto FF, Verrotti A. New developments in the management of partial-onset epilepsy: role of brivaracetam. Drug Des Devel Ther. 2017;11:643–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zelano J, Ben-Menachem E. Eslicarbazepine acetate for the treatment of partial epilepsy. Expert Opin Pharmacother. 2016;17(8):1165–9.

    Article  CAS  PubMed  Google Scholar 

  122. Soares-da-Silva P, Pires N, Bonifácio MJ, et al. Eslicarbazepine acetate for the treatment of focal epilepsy: an update on its proposed mechanisms of action. Pharmacol Res Perspect. 2015;3(2):e00124.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Bialer M, Soares-da-Silva P. Pharmacokinetics and drug interactions of eslicarbazepine acetate. Epilepsia. 2012;53(6):935–46.

    Article  CAS  PubMed  Google Scholar 

  124. Maia J, Almeida L, Falcão A, et al. Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate. Int J Clin Pharmacol Ther. 2008;46(3):119–30.

    Article  CAS  PubMed  Google Scholar 

  125. Falcão A, Vaz-da-Silva M, Gama H, et al. Effect of eslicarbazepine acetate on the pharmacokinetics of a combined ethinylestradiol/levonorgestrel oral contraceptive in healthy women. Epilepsy Res. 2013;105(3):368–76.

    Article  PubMed  CAS  Google Scholar 

  126. Falcão A, Pinto R, Nunes T, Soares-da-Silva P. Effect of repeated administration of eslicarbazepine acetate on the pharmacokinetics of simvastatin in healthy subjects. Epilepsy Res. 2013;106(1–2):244–9.

    Article  PubMed  CAS  Google Scholar 

  127. Almeida L, Minciu I, Nunes T, Butoianu N, Falcão A, Magureanu SA, Soares-da-Silva P. Pharmacokinetics, efficacy, and tolerability of eslicarbazepine acetate in children and adolescents with epilepsy. J Clin Pharmacol. 2008;48(8):966–77.

    Article  CAS  PubMed  Google Scholar 

  128. Galiana GL, Gauthier AC, Mattson RH. Eslicarbazepine acetate: a new improvement on a classic drug family for the treatment of partial-onset seizures. Drugs R D. 2017;17(3):329–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Holtkamp M, McMurray R, Bagul M, et al. Real-world data on eslicarbazepine acetate as add-on to antiepileptic monotherapy. Acta Neurol Scand. 2016;134(1):76–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Rogawski MA, Tofighy A, White HS, et al. Current understanding of the mechanism of action of the antiepileptic drug lacosamide. Epilepsy Res. 2015;110:189–205.

    Article  CAS  PubMed  Google Scholar 

  131. Cawello W, Boekens H, Bonn R. Absorption, disposition, metabolic fate and elimination of the anti-epileptic drug lacosamide in humans: mass balance following intravenous and oral administration. Eur J Drug Metab Pharmacokinet. 2012;37(4):241–8.

    Article  CAS  PubMed  Google Scholar 

  132. Kim JS, Kim H, Lim BC, et al. Lacosamide as an adjunctive therapy in pediatric patients with refractory focal epilepsy. Brain Dev. 2014;36(6):510–5.

    Article  PubMed  Google Scholar 

  133. Cawello W, Mueller-Voessing C, Fichtner A. Pharmacokinetics of lacosamide and omeprazole coadministration in healthy volunteers: results from a phase 1, randomized, crossover trial. Clin Drug Investig. 2014;34(5):317–25.

    Article  CAS  PubMed  Google Scholar 

  134. Cawello W, Rosenkranz B, Schmid B, Wierich W. Pharmacodynamic and pharmacokinetic evaluation of coadministration of lacosamide and oral contraceptive. Epilepsia. 2013;54(3):530–6.

    Article  CAS  PubMed  Google Scholar 

  135. Stockis A, van Lier JJ, Cawello W, et al. Lack of effect of lacosamide on the pharmacokinetic and pharmacodynamic profiles of warfarin. Epilepsia. 2013;54(7):1161–6.

    Article  CAS  PubMed  Google Scholar 

  136. Chong DJ, Lerman AM. Practice update: review of anticonvulsant therapy. Curr Neurol Neurosci Rep. 2016;16(4):39.

    Article  PubMed  CAS  Google Scholar 

  137. Yildiz EP, Ozkan MU, Bektas G, et al. Lacosamide treatment of childhood refractory focal epilepsy: the first reported side effect in paediatric patients. Childs Nerv Syst. 2017;33(11):2023–7.

    Article  PubMed  Google Scholar 

  138. Kellinghaus C. Reversible suicidal ideation after exposure to lacosamide. Seizure. 2013;22(4):318–9.

    Article  PubMed  Google Scholar 

  139. De Liso P, Vigevano F, Specchio N, et al. Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies—an Italian observational multicenter study. Epilepsy Res. 2016;127:93–100.

    Article  PubMed  CAS  Google Scholar 

  140. Biró A, Stephani U, Tarallo T, et al. Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies: first experiences. Neuropediatrics. 2015;46(2):110–6.

    Article  PubMed  CAS  Google Scholar 

  141. Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Curr. 2011;11(2):56–63.

    Article  PubMed  PubMed Central  Google Scholar 

  142. Patsalos PN. The clinical pharmacology profile of the new antiepileptic drug perampanel: a novel noncompetitive AMPA receptor antagonist. Epilepsia. 2015;56(1):12–27.

    Article  CAS  PubMed  Google Scholar 

  143. Kim HD, Chi CS, Desudchit T, et al. Review of clinical studies of perampanel in adolescent patients. Brain Behav. 2016;6(9):e00505.

    Article  PubMed  PubMed Central  Google Scholar 

  144. De Liso P, Moavero R, Coppola G, et al. Current role of perampanel in pediatric epilepsy. Ital J Pediatr. 2017;43(1):51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Yamamoto Y, Usui N, Nishida T, et al. Therapeutic drug monitoring for perampanel in Japanese epilepsy patients: influence of concomitant antiepileptic drugs. Ther Drug Monit. 2017;39(4):446–9.

    Article  CAS  PubMed  Google Scholar 

  146. Rugg-Gunn F. Adverse effects and safety profile of perampanel: a review of pooled data. Epilepsia. 2014;55(s1):13–5.

    Article  CAS  PubMed  Google Scholar 

  147. McLean JM, Schmutz M, Pozza M, Wamil AW. The influence of rufinamide on sodium currents and action potential firing in rodent neurons. Epilepsia. 2005;46:296.

    Google Scholar 

  148. Perucca E, Cloyd J, Crithley D, Fuseau E. Rufinamide: clinical pharmacokinetics and concentration-response relationship in patients with epilepsy. Epilepsia. 2008;49(7):1123–41.

    Article  CAS  PubMed  Google Scholar 

  149. Dahlin MG, Ohman I. Rufinamide in children with refractory epilepsy: pharmacokinetics, efficacy, and safety. Neuropediatrics. 2012;43(5):264–70.

    Article  CAS  PubMed  Google Scholar 

  150. Arzimanoglou A, Ferreira JA, Satlin A, et al. Safety and pharmacokinetic profile of rufinamide in pediatric patients aged less than 4 years with Lennox–Gastaut syndrome: an interim analysis from a multicenter, randomized, active-controlled, open-label study. Eur J Paediatr Neurol. 2016;20(3):393–402.

    Article  PubMed  Google Scholar 

  151. Wisniewski CS. Rufinamide: a new antiepileptic medication for the treatment of seizures associated with Lennox–Gastaut syndrome. Ann Pharmacother. 2010;44(4):658–67.

    Article  CAS  PubMed  Google Scholar 

  152. Biton V. Rufinamide. In: Shorvon S, Perucca E, Engel J, editors. The treatment of epilepsy. 3rd ed. New York: Wiley-Blackwell; 2009. pp. 647–55.

    Book  Google Scholar 

  153. Alsaad AM, Koren G. Exposure to rufinamide and risks of CNS adverse events in drug-resistant epilepsy: a meta-analysis of randomized, placebo-controlled trials. Br J Clin Pharmacol. 2014;78(6):1264–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Xu Z, Zhao H, Chen Z. The efficacy and safety of rufinamide in drug-resistant epilepsy: a meta-analysis of double-blind, randomized, placebo controlled trials. Epilepsy Res. 2016;120:104–10.

    Article  CAS  PubMed  Google Scholar 

  155. Nickels KC, Wirrell EC. Stiripentol in the management of epilepsy. CNS Drugs. 2017;31(5):405–16.

    Article  CAS  PubMed  Google Scholar 

  156. Peigné S, Rey E, Le Guern ME, et al. Reassessment of stiripentol pharmacokinetics in healthy adult volunteers. Epilepsy Res. 2014;108(5):909–16.

    Article  PubMed  CAS  Google Scholar 

  157. Levy RH, Loiseau P, Guyot M, et al. Stiripentol kinetics in epilepsy: nonlinearity and interactions. Clin Pharmacol Ther. 1984;36:661–9.

    Article  CAS  PubMed  Google Scholar 

  158. Inoue Y, Ohtsuka Y, STP-1 Study Group. Long-term safety and efficacy of stiripentol for the treatment of Dravet syndrome: a multicenter, open-label study in Japan. Epilepsy Res. 2015;113:90–7.

    Article  CAS  PubMed  Google Scholar 

  159. Bulitta JB, Holford NHG. Chapter 33: Population pharmacokinetic and pharmacodynamic methods. In: Balakrishnan N, editor. Methods and applications of statistics in clinical trials: planning, analysis, and inferential methods. New York: Wiley; 2008.

    Google Scholar 

  160. Hachad H, Ragueneau-Majlessi I, Levy RH. A useful tool for drug interaction evaluation: the University of Washington Metabolism and Transport Drug Interaction Database. Hum Genom. 2010;5(1):61–72.

    Article  CAS  Google Scholar 

  161. Mould DR, Dubinsky MC. Dashboard systems: pharmacokinetic/pharmacodynamic mediated dose optimization for monoclonal antibodies. J Clin Pharmacol. 2015;55(Suppl 3):S51–9.

    Article  CAS  PubMed  Google Scholar 

  162. Legros B, Boon P, Ceulemans B, et al. Development of an electronic decision tool to support appropriate treatment choice in adultpatients with epilepsy–Epicope®. Seizure. 2012;21(1):32–9.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics, University of L’Aquila, Via Vetoio, 1. Coppito, L’Aquila, Italy

    Giulia Iapadre, Luca Zagaroli & Alberto Verrotti

  2. Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Opthalmology, Genetics, Maternal and Child Health, University of Genoa, “G. Gaslini” Institute, Genoa, Italy

    Ganna Balagura & Pasquale Striano

Authors
  1. Giulia Iapadre
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Ganna Balagura
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Luca Zagaroli
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Pasquale Striano
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Alberto Verrotti
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Alberto Verrotti.

Ethics declarations

Ethical Publication Statement

The authors confirm they have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Funding

No sources of funding were used to conduct this study or prepare this manuscript.

Conflict of interest

Giulia Iapadre, Ganna Balagura, Luca Zagaroli, Pasquale Striano, and Alberto Verrotti have no conflicts of interest that are directly relevant to the content of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iapadre, G., Balagura, G., Zagaroli, L. et al. Pharmacokinetics and Drug Interaction of Antiepileptic Drugs in Children and Adolescents. Pediatr Drugs 20, 429–453 (2018). https://doi.org/10.1007/s40272-018-0302-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40272-018-0302-4