Clinical Pharmacokinetics

, Volume 45, Issue 11, pp 1061–1075 | Cite as

Pharmacokinetic Variability of Newer Antiepileptic Drugs

When is Monitoring Needed?
  • Svein I. Johannessen
  • Torbjörn Tomson
Leading Article


A new generation of antiepileptic drugs (AEDs) has reached the market in recent years with ten new compounds: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide. The newer AEDs in general have more predictable pharmacokinetics than older AEDs such as phenytoin, carbamazepine and valproic acid (valproate sodium), which have a pronounced inter-individual variability in their pharmacokinetics and a narrow therapeutic range. For these older drugs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined ‘therapeutic range’, representing an interval where most patients are expected to show an optimal response. However, such ranges must be interpreted with caution, since many patients are optimally treated when they have serum concentrations below or above the suggested range. It is often said that there is less need for therapeutic drug monitoring (TDM) with the newer AEDs, although this is partially based on the lack of documented correlation between serum concentration and drug effects. Nevertheless, TDM may be useful despite the shortcomings of existing therapeutic ranges, by utilisation of the concept of ‘individual reference concentrations’ based on intra-individual comparisons of drug serum concentrations. With this concept, TDM may be indicated regardless of the existence or lack of a well-defined therapeutic range.

The ten newer AEDs all have different pharmacological properties, and therefore, the usefulness of TDM for these drugs has to be assessed individually. For vigabatrin, a clear relationship between drug concentration and clinical effect cannot be expected because of its unique mode of action. Therefore, TDM of vigabatrin is mainly to check compliance. The mode of action of the other new AEDs would not preclude the applicability of TDM. For the prodrug oxcarbazepine, TDM is also useful, since the active metabolite licarbazepine is measured.

For drugs that are eliminated renally completely unchanged (gabapentin, pregabalin and vigabatrin) or mainly unchanged (levetiracetam and topiramate), the pharmacokinetic variability is less pronounced and more predictable. However, the dose-dependent absorption of gabapentin increases its pharmacokinetic variability. Drug interactions can affect topiramate concentrations markedly, and individual factors such as age, pregnancy and renal function will contribute to the pharmacokinetic variability of all renally eliminated AEDs. For those of the newer AEDs that are metabolised (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide), pharmacokinetic variability is just as relevant as for many of the older AEDs. Therefore, TDM is likely to be useful in many clinical settings for the newer AEDs. The purpose of the present review is to discuss individually the potential value of TDM of these newer AEDs, with emphasis on pharmacokinetic variability.


Gabapentin Lamotrigine Topiramate Pregabalin Therapeutic Drug Monitoring 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflict of interests that are directly relevant to the content of this manuscript.


  1. 1.
    Johannessen SI, Tomson T. General principles. Laboratory monitoring of antiepileptic drugs. In: Levy RM, Mattson RH, Meldrum BS, et al., editors. Antiepileptic drugs. 5th ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2002: 103–11Google Scholar
  2. 2.
    Woo E, Chan YM, Yu YL, et al. If a well-stabilized epileptic patient has a subtherapeutic antiepileptic drug level, should the dose be increased? A randomized prospective study. Epilepsia 1988; 29: 129–39PubMedCrossRefGoogle Scholar
  3. 3.
    Kozer E, Parvez S, Minassian BA, et al. How high can we go with phenytoin? Ther Drug Monit 2002; 24: 386–9PubMedCrossRefGoogle Scholar
  4. 4.
    Perucca E. Is there a role for therapeutic drug monitoring of new anticonvulsants? Clin Pharmacokinet 2000; 38: 191–204PubMedCrossRefGoogle Scholar
  5. 5.
    Kleckner NW, Glazewski JC, Chen CC, et al. Subtype-selective antagonism of N-methyl-D-aspartate receptors by felbamate: insights into the mechanism of action. J Pharmacol Exp Ther 1999; 289: 886–94PubMedGoogle Scholar
  6. 6.
    Schumaker RC, Fantel C, Kelton E, et al. Evaluation of the elimination of 14C felbamate in healthy men [abstract]. Epilepsia 1990; 31: 642Google Scholar
  7. 7.
    Palmer KJ, McTavish D. Felbamate: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in epilepsy. Drugs 1993; 45: 1041–65PubMedCrossRefGoogle Scholar
  8. 8.
    Thompson CD, Gulden PH, Macdonald TL. Identification of modified atropaldehyde mercapturic acids in rat and human urine after felbamate administration. Chem Res Toxicol 1997; 10: 457–62PubMedCrossRefGoogle Scholar
  9. 9.
    Thompson CD, Kinter MT, Macdonald TL. Synthesis and in vitro reactivity of 3-carbamoyl-2-phenylpropionaldehyde and 2-phenylpropenal: putative reactive metabolites of felbamate. Chem Res Toxicol 1996; 9: 1225–9PubMedCrossRefGoogle Scholar
  10. 10.
    Kapetanovic IM, Torchin CD, Thompson CD, et al. Potentially reactive cyclic carbamate metabolite of the antiepileptic drug felbamate produced by human liver tissue in vitro. Drug Metab Dispos 1998; 26: 1089–95PubMedGoogle Scholar
  11. 11.
    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: 19–29PubMedCrossRefGoogle Scholar
  12. 12.
    Richens A, Banfield CR, Salfi M, et al. Single and multiple dose pharmacokinetics of felbamate in the elderly. Br J Clin Pharmacol 1997; 44: 129–34PubMedCrossRefGoogle Scholar
  13. 13.
    Glue P, Sulowicz W, Colucci R, et al. Single-dose pharmacokinetics of felbamate in patients with renal dysfunction. Br J Clin Pharmacol 1997; 44: 91–3PubMedCrossRefGoogle Scholar
  14. 14.
    Wilensky AJ, Friel PN, Ojemann LM, et al. Pharmacokinetics of W-554 (ADD 03055) in epileptic patients. Epilepsia 1985; 26: 602–6PubMedCrossRefGoogle Scholar
  15. 15.
    Wagner ML, Graves NM, Marienau K, et al. Discontinuation of phenytoin and carbamazepine in patients receiving felbamate. Epilepsia 1991; 32: 398–406PubMedCrossRefGoogle Scholar
  16. 16.
    Leppik IE, Dreifuss FE, Pledger GW, et al. Felbamate for partial seizures: results of a controlled clinical trial. Neurology 1991; 41: 1785–9PubMedCrossRefGoogle Scholar
  17. 17.
    Harden CL, Trifiletti R, Kutt H. Felbamate levels in patients with epilepsy. Epilepsia 1996; 37: 280–3PubMedCrossRefGoogle Scholar
  18. 18.
    Johannessen SI, Battino D, Berry DJ, et al. Therapeutic drug monitoring of the newer antiepileptic drugs. Ther Drug Monit 2003; 25: 347–63PubMedCrossRefGoogle Scholar
  19. 19.
    Johannessen SI. Can pharmacokinetic variability be controlled for the patient’s benefit: the place of TDM for new AEDs. Ther Drug Monit 2005; 27: 710–3PubMedCrossRefGoogle Scholar
  20. 20.
    Petroff OAC, Rothman DL, Behar KL, et al. The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol 1996; 39: 95–9PubMedCrossRefGoogle Scholar
  21. 21.
    Goa KL, Sorkin EM. Gabapentin: a review of its pharmacological properties and clinical potential in epilepsy. Drugs 1993; 46: 409–27PubMedCrossRefGoogle Scholar
  22. 22.
    Vollmer KO, Anhut H, Thomann P, et al. Pharmacokinetic model and absolute bioavailability of the new anticonvulsant gabapentin. In: Manelis J, Bental E, Loeber JN, et al., editors. Advances in epileptology. New York: Raven Press, 1989: 209–11Google Scholar
  23. 23.
    Vollmer KO, von Hodenberg A, Kö;lle EU. Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Arzneim Forsch 1986; 36: 830–9Google Scholar
  24. 24.
    Turck D, Vollmer KO, Brockbrader H, et al. Dose-linearity of the new anticonvulsant gabapentin after multiple oral doses. Eur J Clin Pharmacol 1989; 36 Suppl.: A310Google Scholar
  25. 25.
    Stewart BH, Kugler AR, Thompson PR, et al. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of lack of proportionality between increasing dose and drug levels in plasma. Pharm Res 1993; 10: 276–81PubMedCrossRefGoogle Scholar
  26. 26.
    Besag FMC, Berry DJ, Aylett SA, et al. Serum gabapentin levels continue to increase with dose in the high-range in children and teenagers. Epilepsia 2000; 41 (Suppl. Florence): 147CrossRefGoogle Scholar
  27. 27.
    Ouellet D, Bockbrader HN, Wesche DL, et al. Population pharmacokinetics of gabapentin in infants and children. Epilepsy Res 2001; 47: 229–41PubMedCrossRefGoogle Scholar
  28. 28.
    Armijo JA, Pena MA, Adin J, et al. Association between patient age and gabapentin serum concentrations-to-dose ratio: a preliminary multivariate analysis. Ther Drug Monit 2004; 26: 633–7PubMedCrossRefGoogle Scholar
  29. 29.
    McLean MJ. Gabapentin. Epilepsia 1995; 36 Suppl. 2: S57–86CrossRefGoogle Scholar
  30. 30.
    Gatti G, Ferrari AR, Guerrini R, et al. Plasma gabapentin concentrations in children with epilepsy: influence of age, relationship with dosage, and preliminary observations on correlation with clinical response. Ther Drug Monit 2003; 25: 54–60PubMedCrossRefGoogle Scholar
  31. 31.
    Lindberger M, Luhr O, Johannessen SI, et al. Serum concentration and effects of gabapentin and vigabatrin: observations from a dose titration study. Ther Drug Monit 2003; 4: 457–62CrossRefGoogle Scholar
  32. 32.
    Xie X, Hagan RM. Cellular and molecular actions of lamotrigine: possible mechanisms of efficacy in bipolar disorder. Neuropsychobiology 1998; 38: 119–30PubMedCrossRefGoogle Scholar
  33. 33.
    Fitton A, Goa K. Lamotrigine: an update of its pharmacology and therapeutic use in epilepsy. Drugs 1995; 50: 691–13PubMedCrossRefGoogle Scholar
  34. 34.
    Dickens M, Chen C. Lamotrigine: chemistry, biotransformation, and pharmacokinetics. In: Levy RH, Mattson RH, Meldrum BS, et al., editors. Antiepileptic drugs. 5th ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2002: 370–9Google Scholar
  35. 35.
    Hussein Z, Posner J. Population pharmacokinetics of lamotrigine monotherapy in patients with epilepsy: retrospective analysis of routine monitoring data. Br J Clin Pharmacol 1997; 43: 457–65PubMedCrossRefGoogle Scholar
  36. 36.
    Öhman I, Vitols S, Tomson T. Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia 2000; 41: 709–13PubMedCrossRefGoogle Scholar
  37. 37.
    Mikati MA, Fayad M, Koleilat M, et al. Efficacy, tolerability, and kinetics of lamotrigine in infants. J Pediatr 2002; 141:31–5PubMedCrossRefGoogle Scholar
  38. 38.
    Eriksson AS, Hoppu K, Nergârdh A, et al. Pharmacokinetic interactions between lamotrigine and other antiepileptic drugs in children with intractable epilepsy. Epilepsia 1996; 37: 769–73PubMedCrossRefGoogle Scholar
  39. 39.
    Bartoli A, Guerrini R, Belmonte A, et al. The influence of dosage, age and comedication on steady-state plasma lamotrigine concentrations in epileptic children: a prospective study with preliminary assessment of correlations with clinical response. Ther Drug Monit 1997; 19: 252–60PubMedCrossRefGoogle Scholar
  40. 40.
    Armijo JA, Btavo J, Cuadrado B, et al. Lamotrigine serum concentration-to-dose ratio: influence of age and concomitant antiepileptic drugs and dosage implications. Ther Drug Monit 1999; 21: 182–90PubMedCrossRefGoogle Scholar
  41. 41.
    Chen C, Casale EJ, Duncan B, et al. Pharmacokinetics of lamotrigine in children in the absence of other antiepileptic drugs. Pharmacotherapy 1999; 19: 437–41PubMedCrossRefGoogle Scholar
  42. 42.
    Battino D, Croci D, Granata T, et al. Single-dose pharmacokinetics of lamotrigine in children: influence of age and comedication. Ther Drug Monit 2001; 23: 217–22PubMedCrossRefGoogle Scholar
  43. 43.
    Posner J, Holdich T, Crome P. Comparison of lamotrigine pharmacokinetics in young and elderly healthy volunteers. J Pharmacol Med 1991; 18: 19–29Google Scholar
  44. 44.
    Tran TA, Leppik IE, Blesi K, et al. Lamotrigine clearance during pregnancy. Neurology 2002; 59: 251–5PubMedCrossRefGoogle Scholar
  45. 45.
    de Haan GJ, Edelbroek P, Segers J, et al. Gestation-induced changes in lamotrigine pharmacokinetics: a monotherapy study. Neurology 2004; 63: 571–3PubMedCrossRefGoogle Scholar
  46. 46.
    Pennell PB, Newport DJ, Stowe ZN, et al. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology 2004; 62: 292–5PubMedCrossRefGoogle Scholar
  47. 47.
    Fillastre JP, Taubert AM, Fialaire A, et al. Pharmacokinetics of lamotrigine in patients with renal impairment: influence of haemodialysis. Drug Exp Clin Res 1993; 19: 25–32Google Scholar
  48. 48.
    May TW, Rambeck B, Jurgens U. Influence of oxcarbazepine and methosuximide in lamotrigine concentrations in epileptic patients with or without valproic acid comedication: results of a retrospective study. Ther Drug Monit 1999; 21: 175–81PubMedCrossRefGoogle Scholar
  49. 49.
    Wnuk W, Volanski A, Foletti G. Topiramate decreases lamotrigine concentrations [abstract]. Ther Drug Monit 1999; 21: 449CrossRefGoogle Scholar
  50. 50.
    Ebert U, Thong NQ, Oertel R, et al. Effects of rifampicin and cimetidine on pharmacokinetics and pharmacodynamics of lamotrigine in healthy subjects. Eur J Clin Pharmacol 2000; 56: 299–304PubMedCrossRefGoogle Scholar
  51. 51.
    Sabers A, Öhman I, Christensen J, et al. Oral contraceptives reduce lamotrigine plasma levels. Neurology 2003; 61: 570–1PubMedCrossRefGoogle Scholar
  52. 52.
    Reimers A, Helde G, Brodtkorb E. Ethinyl estradiol, not progestogens, reduces lamotrigine serum concentrations. Epilepsia 2005 Sep; 46(9): 1414–7PubMedCrossRefGoogle Scholar
  53. 53.
    Sidhu J, Job S, Singh S, et al. The co-administration of lamotrigine and a combined oral contraceptive in healthy female subjects. Br J Clin Pharmacol 2006; 61: 191–9PubMedCrossRefGoogle Scholar
  54. 54.
    Yuen AWC, Land G, Weatherley BC, et al. Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992; 33: 511–3PubMedCrossRefGoogle Scholar
  55. 55.
    Anderson GD, Yau MK, Gidal BE, et al. Bidirectional interaction of valproate and lamotrigine in healthy subjects. Clin Pharmacol Ther 1996; 60: 145–56PubMedCrossRefGoogle Scholar
  56. 56.
    Kaufman KR, Gemer R. Lamotrigine toxicity secondary to setraline. Seizure 1998; 7: 163–5PubMedGoogle Scholar
  57. 57.
    Hirsch LJ, Weintraub AB, Buschbaum R, et al. Correlating lamotrigine serum concentrations with tolerability in patients with epilepsy. Neurology 2004; 63: 1022–6PubMedCrossRefGoogle Scholar
  58. 58.
    Morris RG, Lee MY, Cleanthous X, et al. Long-term follow-up using a higher target range for lamotrigine monitoring. Ther Drug Monit 2004; 26: 626–32PubMedCrossRefGoogle Scholar
  59. 59.
    Noyer M, Gillard M, Matagne A, et al. The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes. Eur J Pharmacol 1995; 286: 137–46PubMedCrossRefGoogle Scholar
  60. 60.
    Klitgaard H. Levetiracetam: the preclinical profile of a new class of antiepileptic drugs. Epilepsia 2001; 42 Suppl. 4: 13–8PubMedCrossRefGoogle Scholar
  61. 61.
    Bialer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs: a summary of the seventh Eilat conference (EILAT VII). Epilepsy Res 2004; 61: 1–48PubMedCrossRefGoogle Scholar
  62. 62.
    Patsalos PN. Pharmacokinetics profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000; 85: 77–85PubMedCrossRefGoogle Scholar
  63. 63.
    Radtke RA. Pharmacokinetics of levetiracetam. Epilepsia 2001; 42 Suppl. 4: 24–7PubMedCrossRefGoogle Scholar
  64. 64.
    May TW, Rambeck B, Jürgens U. Serum concentrations of levetiracetam in epileptic patients: the influence of dose and co-medication. Ther Drug Monit 2003; 25: 690–9PubMedCrossRefGoogle Scholar
  65. 65.
    Pennell PB, Roganti A, Helmers S, et al. The impact of pregnancy and childbirth on the elimination of levetiractem [abstract]. Epilepsia 2005; 46 Suppl. 8: 89Google Scholar
  66. 66.
    French J. Use of levetiracetam in special populations. Epilepsia 2001; 42 Suppl. 4: 24–7CrossRefGoogle Scholar
  67. 67.
    Contin M, Albani F, Riva R, et al. Levetiracetam therapeutic monitoring in patients with epilepsy and effect of concomitant antiepileptic drugs. Ther Drug Monit 2004; 26: 375–9PubMedCrossRefGoogle Scholar
  68. 68.
    Kubova H, Mares P. Anticonvulsant action of oxcarbazepine, hydroxycarbazepine and carbamazepine against metrazol-induced motor seizures in developing rats. Epilepsia 1993; 34: 188–92PubMedCrossRefGoogle Scholar
  69. 69.
    White HS. Comparative anticonvulsant and mechanistic profile of the established and newer antiepileptic drugs. Epilepsia 1999; 40 Suppl. 5: S2–S10PubMedCrossRefGoogle Scholar
  70. 70.
    Calabresi P, De Murtas M, Stefani A, et al. Action of GP 47779 the active metabolite of oxcarbazepine, on the corticostriatal system: I. Modulation of corticostriatal synaptic transmission. Epilepsia 1995; 36: 990–6PubMedCrossRefGoogle Scholar
  71. 71.
    Lloyd P, Flesch G, Dieterle W. Clinical pharmacology and pharmacokinetics of oxcarbazepine. Epilepsia 1994; 35 Suppl. 3: S10–3PubMedCrossRefGoogle Scholar
  72. 72.
    Volosov A, Xiaodong S, Perucca E, et al. Enantioselective pharmacokinetics of 10-hydroxycarbazepine after oral administration of oxcarbazepine to healthy Chinese subjects. Clin Pharmacol Ther 1999; 66: 547–53PubMedGoogle Scholar
  73. 73.
    Volosov A, Bialer M, Xiaodong S, et al. Simultaneous stereoselective high-performance liquid Chromatographic determination of 10-hydroxycarbazepine and its metabolite carbamazepine-10,ll-trans-dihydrol in human urine. J Chromatog B Biomed Sci Appl 2000; 738: 419–25CrossRefGoogle Scholar
  74. 74.
    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: 341–69PubMedCrossRefGoogle Scholar
  75. 75.
    Wellington K, Goa KL. Oxcarbazepine: an update of its efficacy in the management of epilepsy. CNS Drugs 2001; 15: 137–63PubMedCrossRefGoogle Scholar
  76. 76.
    Baruzzi A, Albani F, Riva R. Oxcarbazepine: pharmacokinetic interactions and their clinical relevance. Epilepsia 1994; 35 Suppl. 3: 9S–14SCrossRefGoogle Scholar
  77. 77.
    Sallas WM, Milosavljev S, D’souza J, et al. Pharmacokinetic drug interactions in children taking oxcarbazepine. Clin Pharmacol Ther 2003; 74: 138–49PubMedCrossRefGoogle Scholar
  78. 78.
    Rey E, Bulteau CF, Motte J, et al. Oxcarbazepine pharmacokinetics and tolerability in children with inadequately controlled epilepsy. J Clin Pharmacol 2004; 44: 1290–300PubMedCrossRefGoogle Scholar
  79. 79.
    Van Henningen PNM, Eve MD, Oosterhuis B, et al. The influence of age on the pharmacokinetics of the antiepileptic agent oxcarbazepine. Clin Pharmacol Ther 1991; 50: 410–9CrossRefGoogle Scholar
  80. 80.
    Mazzucchelli I, Onat FY, Ozkara C, et al. Changes in disposition of oxcarbazepine and its metabolites during pregnancy and the puerperium. Epilepsia 2006; 47: 504–9PubMedCrossRefGoogle Scholar
  81. 81.
    Rouan MC, Lecaillon JB, Godbillon J, et al. The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites. Eur J Clin Pharmacol 1994; 47: 161–7PubMedCrossRefGoogle Scholar
  82. 82.
    Tartara A, Galimberti CA, Manni R, et al. The pharmacokinetic profile of oxcarbazepine and its active metabolite 10-hydroxy-carbazepien in normal subjects and in epileptic patients treated with phenobarbitone and valproic acid. Br J Clin Pharmacol 1993; 36: 366–8PubMedCrossRefGoogle Scholar
  83. 83.
    McKee PJ, Blacklaw J, Forrest G, et al. A double-blind, placebo-controlled interaction study between oxcarbazepine and carbamazepine, sodium valproate and phenytoin in epileptic patients. Br J Clin Pharmacol 1994; 37: 27–32PubMedCrossRefGoogle Scholar
  84. 84.
    Armijo JA, Vega-Gil N, Shushtarian M, et al. 10-Hydroxycarbazepine seram concentration-to-oxcarbazepine dose ratio: influence of age and concomitant antiepileptic drugs. Ther Drug Monit 2005; 27: 199–204PubMedCrossRefGoogle Scholar
  85. 85.
    Keranen T, Jolkkonen J, Jensen PK, et al. Absence of interaction between oxcarbazepine and erythromycin. Acta Neurol Scand 1992; 86: 120–3PubMedCrossRefGoogle Scholar
  86. 86.
    Morgensen PH, Jörgensen L, Boas J, et al. Effects of dextropropoxyphene on stead-state kinetics of oxcarbazepine and its metabolites. Acta Neurol Scand 1992; 85: 14–7CrossRefGoogle Scholar
  87. 87.
    Baruzzi A, Albani F, Riva R. Oxcarbazepine: pharmacokinetic interactions and their clinical significance. Epilepsia 1994; 35 Suppl. 3: S14–9PubMedCrossRefGoogle Scholar
  88. 88.
    Friis ML, Kristensen O, Boas J, et al. Therapeutic experiences with 947 epileptic out-patients in oxcarbazepine treatment. Acta Neurol Scand 1993; 87: 224–7PubMedCrossRefGoogle Scholar
  89. 89.
    Van Parys JAP, Meinardi H. Survey of 260 patients treated with oxcarbazepine (Trileptal) on a named-patient basis. Epilepsy Res 1994; 19: 79–85PubMedCrossRefGoogle Scholar
  90. 90.
    Borusiak P, Korn-Merker E, Holert N, et al. Oxcarbazepine in treatment of childhood epilepsy: a survey of 46 children and adolescents. J Epilepsy 1998; 11: 355–60CrossRefGoogle Scholar
  91. 91.
    Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia 2004; 45 Suppl. 6: 13–8PubMedCrossRefGoogle Scholar
  92. 92.
    Warner G, Figgitt DP. Pregabalin: as adjunctive treatment of partial seizures. CNS Drugs 2005; 19(3): 265–72PubMedCrossRefGoogle Scholar
  93. 93.
    Berry D, Millington C. Analysis of pregabalin at therapeutic concentrations in human plasma/serum by reversed-phased HPLC. Ther Drug Monit 2005; 27: 451–6PubMedCrossRefGoogle Scholar
  94. 94.
    Czuczwar SJ, Patsalos PN. The new generation of GABA enhancers: potential in the treatment of epilepsy. CNS Drugs 2001; 15: 339–50PubMedCrossRefGoogle Scholar
  95. 95.
    Wang X, Patsalos PN. The pharmacokinetic profile of tiagabine. Rev Contemp Pharmacother 2002; 12: 225–33Google Scholar
  96. 96.
    Gustavson LE, Boeller SW, Granneman GR, et al. A single-dose study to define tiagabine pharmacokinetics in pediatric patients with complex partial seizures. Neurology 1997; 48: 1032–7PubMedCrossRefGoogle Scholar
  97. 97.
    Tomson T. Gender aspects of pharmacokinetics of new and old AEDs: pregnancy and breast-feeding. Ther Drug Monit 2005; 27: 718–21PubMedCrossRefGoogle Scholar
  98. 98.
    Lau AH, Gustavson LE, Sperelakis R, et al. Pharmacokinetics and safety of tiagabine in subjects with various degrees of hepatic function. Epilepsia 1997; 38: 445–51PubMedCrossRefGoogle Scholar
  99. 99.
    Adkins JC, Noble S. Tiagabine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of epilepsy. Drugs 1998; 55: 437–60PubMedCrossRefGoogle Scholar
  100. 100.
    So EL, Wolff D, Graves NM, et al. Pharmacokinetics of tiagabine as add-on therapy in patients taking enzyme-inducing antiepilepsy drugs. Epilepsy Res 1995; 22: 221–6PubMedCrossRefGoogle Scholar
  101. 101.
    Williams J, Bialer M, Johannessen SI, et al. Interlaboratory variability in the quantification of new generation antiepileptic drugs based on external quality assessment data. Epilepsia 2003; 44: 40–5PubMedCrossRefGoogle Scholar
  102. 102.
    Rowan AJ, Gustavson I, Shu V, et al. Dose concentration relationship in a multicenter tiagabine (Gabitril) trial [abstract]. Epilepsia 1997; 38 Suppl. 3: 40CrossRefGoogle Scholar
  103. 103.
    Schmidt D, Gram L, Brodie M, et al. Tiagabine in the treatment of epilepsy: a clinical review with a guide for the prescribing physician. Epilepsy Res 2000; 41: 245–51PubMedCrossRefGoogle Scholar
  104. 104.
    Langtry HD, Gillis JC, Davis R. Topiramate: a review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of epilepsy. Drugs 1997; 54: 752–73PubMedCrossRefGoogle Scholar
  105. 105.
    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 Drug Monit 2003; 25: 700–8PubMedCrossRefGoogle Scholar
  106. 106.
    Adin J, Gomez MC, Blanco Y, et al. Topiramate serum concentration-to-dose ratio: influence of age and concomitant antiepileptic drugs and monitoring implications. Ther Drug Monit 2004; 26: 251–7PubMedCrossRefGoogle Scholar
  107. 107.
    Dahlin MG, Öhman IK. Age and antiepileptic drugs influence topiramate plasma levels in children. Pediatr Neurol 2004; 4: 248–53CrossRefGoogle Scholar
  108. 108.
    Bialer M, Doose DR, Murthy B, et al. Pharmacokinetic interactions of topiramate. Clin Pharmacokinet 2004; 43: 763–80PubMedCrossRefGoogle Scholar
  109. 109.
    Battino D, Croci D, Rossini A, et al. Topiramate pharmacokinetics in children and adults with epilepsy: a case-matched comparison based on therapeutic drug monitoring data. Clin Pharmacokinet 2005; 44: 407–16PubMedCrossRefGoogle Scholar
  110. 110.
    Gisclon LG, Riffitts JM, Sica DA, et al. The pharmacokinetics of topiramate in subjects with renal impairment as compared to matched subjects with normal renal function [abstract]. Pharm Res 1993; 10 Suppl. 10: S397Google Scholar
  111. 111.
    Rosenberg WE, Liao S, Kramer LD, et al. Comparison of the steady-state pharmacokinetics of topiramate and valproate in patients with epilepsy during monotheraphy and concomitant therapy. Epilepsia 1997; 38: 324–33CrossRefGoogle Scholar
  112. 112.
    Stephen LJ, Sills GJ, Brodie MJ. Topiramate in refractory epilepsy: a prospective observational study. Epilepsia 2000; 41: 977–80PubMedCrossRefGoogle Scholar
  113. 113.
    Christensen J, Poulsen JH, Andreasen F, et al. Topiramate addon treatment in refractory epilepsy patients: a randomised concentration controlled clinical trial [abstract]. Epilepsia 2001; 42 Suppl. 7: 178Google Scholar
  114. 114.
    Christensen J, Andreassen F, Poulsen JH, et al. Randomized, concentration-controlled trial of topiramate in refractory focal epilepsy. Neurology 2003; 61: 1210–8PubMedCrossRefGoogle Scholar
  115. 115.
    Zanotta N, Raggi ME, Radice L, et al. Clinical experience with topiramate dosing and serum levels in patients with epilepsy. Seizure 2006 (Epub ahead of print)Google Scholar
  116. 116.
    Wheless JW, Nye JS, Wang S. Topiramate monotherapy: Plasma concentration vs therapeutic effect [abstract]. Epilepsia 2005; 46: 220Google Scholar
  117. 117.
    Preece NE, Jackson GD, Houseman JA, et al. Nuclear magnetic resonance detection of increased GABA in vigabatrin-treated rats in vivo. Epilepsia 1994; 35: 431–6PubMedCrossRefGoogle Scholar
  118. 118.
    Schechter PJ. Clinical pharmacology of vigabatrin. Br J Clin Pharmacol 1989; 27: 19S–22PubMedCrossRefGoogle Scholar
  119. 119.
    Patsalos PN, Duncan JS. The pharmacology and pharmacokinetics of vigabatrin. Rev Contemp Pharmacother 1995; 6: 447–56Google Scholar
  120. 120.
    Armijo JA, Cuadrado A, Bravo J, et al. Vigabatrin serum concentration to dosage ratio: influence of age and associated antiepileptic drugs. Ther Drug Monit 1997; 19: 491–8PubMedCrossRefGoogle Scholar
  121. 121.
    Gatti G, Bartoli A, Marchiselli R, et al. Vigabatrin-induced decrease in serum concentration does not involve a change in phenytoin bioavailability. Br J Clin Pharmacol 1993; 36: 603–5PubMedCrossRefGoogle Scholar
  122. 122.
    Schauf CL. Zonisamide enhances slow sodium inactivation in Myxicola. Brain Res 1987; 413: 185–8PubMedCrossRefGoogle Scholar
  123. 123.
    Suzuki S, Kawakami K, Nishimura S, et al. Zonisamide blocks T-type calcium channel in cultured neurons of rat cerebral cortex. Epilepsy Res 1992; 12: 21–7PubMedCrossRefGoogle Scholar
  124. 124.
    Mori A, Node Y, Packer I. The anticonvulsant zonisamide scavenges free radicals. Epilepsy Res 1998; 30: 153–8PubMedCrossRefGoogle Scholar
  125. 125.
    Perucca E, Bialer M. The clinical pharmacokinetics of the newer antiepileptic drugs: focus on topiramate, zonisamide and tiagabine. Clin Pharmacokinet 1996; 31: 29–46PubMedCrossRefGoogle Scholar
  126. 126.
    Seino M, Naruto S, Ito T, et al. Zonisamide. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven Press, 1995: 1011–24Google Scholar
  127. 127.
    Miura H. Zonisamide monotherapy with once-daily dosing in children with cryptogenic localization-related epilepsies: clinical effects and pharmacokinetic studies. Seizure 2004; 13 Suppl. 5: S17–23PubMedCrossRefGoogle Scholar
  128. 128.
    Peters DH, Sorkin EM. Zonisamide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs 1993; 45: 760–87PubMedCrossRefGoogle Scholar
  129. 129.
    Levy RH, Ragueneau-Majlessi I, Brodie MJ, et al. Lack of clinically significant pharmacokinetic interactions between zonisamide and lamotrigine at steady state in patients with epilepsy. Ther Drug Monit 2005; 27: 193–8PubMedCrossRefGoogle Scholar
  130. 130.
    Mimaki T. Clinical pharmacology and therapeutic drug monitoring of zonisamide. Ther Drug Monit 1998; 20: 593–7PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.The National Center for EpilepsySandvikaNorway
  2. 2.Karolinska InstituteKarolinska University HospitalStockholmSweden

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