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Harnessing the Clinical Potential of Antiepileptic Drug Therapy

Dosage Optimisation

  • Therapy in Practice
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Abstract

For patients with epilepsy, effective seizure control is the most important determinant of good quality of life. To achieve this, antiepileptic drug (AED) dosages should be individualised to maximise therapeutic benefit and to avoid most — if not all — adverse effects. Several studies suggest that, in routine clinical practice, dosage individualisation is often suboptimal. This may lead to patients receiving unnecessarily large dosages. Conversely, it may lead to patients switching to an alternative therapy (when clinical response is deemed insufficient), without exploration of the full dosage range. Indeed, dosage optimisation — which should involve consideration of the treatment setting and individual patient characteristics — can be a complicated process requiring skill and patience.

In general neurological practice, most AEDs should be started at a low dosage and gradually titrated upwards. Starting dosages are similar in most types of epilepsy; however, if a rapid onset of therapeutic action is required, phenytoin, phenobarbital (phenobarbitone), levetiracetam and gabapentin are probably the best tolerated AEDs for starting at full dosage.

The initial target maintenance dosage of an AED should be based on the dose-response profile of the drug, and on specific patient characteristics. Usually, the lowest effective daily dose expected to provide seizure control should be used, although various factors (e.g. stage and severity of epilepsy, pharmacokinetic and pharmacodynamic considerations, attitude of the patient) will markedly influence dosage selection. If seizures are not controlled on the initial target dose, the dosage should be increased gradually until complete seizure control is achieved or intolerable adverse effects occur. In most patients who fail to respond to the initially prescribed drug, switching to another AED (monotherapy) is the best option. Combination therapy may be appropriate for patients unresponsive to 2 or more sequential monotherapies.

Therapeutic drug monitoring (measurement of serum drug concentrations) is useful in various settings, such as when drug interactions are expected, toxicity is suspected, or when AEDs with nonlinear pharmacokinetics (e.g. phenytoin, carbamazepine) are used. No indications currently exist for routine therapeutic drug monitoring of the newer AEDs.

In summary, dosage regimens of AEDs should be assessed regularly, and adjusted if necessary, so that patients can derive optimal therapeutic benefit. For patients considered ‘difficult to treat’ (i.e. those in whom seizures remain incompletely controlled after several attempts at treatment), referral to a specialist is recommended.

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References

  1. Perucca E. Principles of drug treatment. In: Shorvon S, Dreifuss S, Fish DF, et al., editors. The treatment of epilepsy. Oxford: Blackwell Science Ltd, 1996: 152–68

    Google Scholar 

  2. Beghi E, Perucca E. The management of epilepsy in the 1990s: acquisitions, uncertainties, and priorities for future research. Drugs 1995 May; 49(5): 680–94

    Article  PubMed  CAS  Google Scholar 

  3. Perucca E, Richens A. Antiepileptic drugs: clinical aspects. In: Richens A, Marks V, editors. Therapeutic drug monitoring. Edinburgh: Churchill Livingstone, 1981: 320–48

    Google Scholar 

  4. Perucca E, Richens A. Biotransformation. In: Levy RH, Mattson RH, Meldrum B, editors. Antiepileptic drugs. New York: Raven Press, 1995: 31–50

    Google Scholar 

  5. Perucca E. Pharmacokinetics. In: Engel Jr J, Pedley TA, editors. Epilepsy — a comprehensive textbook. New York: Raven Press, 1997: 1131–53

    Google Scholar 

  6. Patsalos PN. Antiepileptic drug pharmacogenetics. Ther Drug Monit 2000 Feb; 22(1): 127–30

    Article  PubMed  CAS  Google Scholar 

  7. Kupfer A, Branch RA. Stereoselective mephobarbital hydroxylation cosegregates with mephenytoin hydroxylation. Clin Pharmacol Ther 1985 Oct; 38(4): 414–8

    Article  PubMed  CAS  Google Scholar 

  8. Mamiya K, Ieiri I, Shimamoto J, et al. The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adultpatients with epilepsy: studies in stereo-selective hydroxylation and population pharmacokinetics. Epilepsia 1998 Dec; 39(12): 1317–23

    Article  PubMed  CAS  Google Scholar 

  9. Perucca E. Is there a role for therapeutic drug monitoring of new anticonvulsants? Clin Pharmacokinet 2000 Mar; 38(3): 191–204

    Article  PubMed  CAS  Google Scholar 

  10. Schmidt D, Haenel F. Therapeutic plasma levels of phenytoin, phenobarbital and carbamazepine: individual variation in relation to seizure frequency and type. Neurology 1984 Sep; 34(9): 1252–5

    Article  PubMed  CAS  Google Scholar 

  11. Koch-Weser J. The serum level approach to individualization of drug dosage. EurJ Clin Pharmacol 1975 Oct 10; 9(1): 1–8

    Article  CAS  Google Scholar 

  12. Lund L. Anticonvulsant effects of diphenylhydantoin relative to plasma levels: a prospective three-year study in ambulant patients with generalized epileptic seizures. Arch Neurol 1974 Nov; 31(5): 289–94

    Article  PubMed  CAS  Google Scholar 

  13. Perucca E. Pharmacoresistance in epilepsy: how should it be defined? CNS Drugs 1998; 10: 171–9

    Article  Google Scholar 

  14. Hermanns G, Noachtar S, Toxhorn I, et al. Systematic testing of medical intractability for carbamazepine, phenytoin, phenobarbital or primidone in monotherapy for patients considered for epilepsy surgery. Epilepsia 1996 Jul; 37(7): 675–9

    Article  PubMed  CAS  Google Scholar 

  15. Perucca E. The new generation of antiepileptic drugs: advantages and disadvantages. Br J Clin Pharmacol 1996; 42: 531–43

    PubMed  CAS  Google Scholar 

  16. Perucca E, Tomson T. Monotherapy trials with the new antiepileptic drugs: study designs, practical relevance and ethical implications. Epilepsy Res 1999 Feb; 33(2-3): 247–62

    Article  PubMed  CAS  Google Scholar 

  17. International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use. Guideline for industry. Dose-response information to support drug registration. ICH-E4. Federal Register 1994; 59: 55972–6

    Google Scholar 

  18. Baldassarre JS, Pledger GW. Clinical trial design for new antiepileptic drugs: determination of dose and titration schedules. Rev Contemp Pharmacother 1999; 10: 133–45

    CAS  Google Scholar 

  19. Chiron C, Dulac O, Gram L. Vigabatrin withdrawal randomized study in children. Epilepsy Res 1996 Nov; 25(3): 209–15

    Article  PubMed  CAS  Google Scholar 

  20. Cramer JA, Fisher R, Ben-Menachem E, et al. New antiepileptic drugs: comparison of key clinical trials. Epilepsia 1999 May; 40(5): 590–600

    Article  PubMed  CAS  Google Scholar 

  21. Perucca E, Beghi E, Dulac O, et al. Assessing risk to benefit ratio in antiepileptic drug therapy. Epilepsy Res 2000 Sep; 41(2): 107–39

    Article  PubMed  CAS  Google Scholar 

  22. Tomson T, Johannessen SI. Therapeutic monitoring of the new antiepileptic drugs. Eur J Clin Pharmacol 2000 Jan; 55(10): 697–705

    Article  PubMed  CAS  Google Scholar 

  23. Richens A, Davidson DLW, Cartlidge NEF, et al. A multicentre comparative trial of sodium valproate and carbamazepine in adult-onset epilepsy. J Neurol Neurosurg Psychiatry 1994 Jun; 57(6): 682–7

    Article  PubMed  CAS  Google Scholar 

  24. Verity CM, Hosking G, Easter DJ, on behalf of the Paediatric EPITEG Collaborative Group. A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. Dev Med Child Neurol 1995 Feb; 37(2): 97–108

    Article  PubMed  CAS  Google Scholar 

  25. Camfield C, Camfield P, Gordon K, et al. Does the number of seizures before treatment influence ease of control or remission of childhood epilepsy? Not if the number is 10 or less. Neurology 1996 Jan; 46(1): 41–4

    Article  PubMed  CAS  Google Scholar 

  26. Shinnar S, Berg AT. Does antiepileptic drug therapy prevent the development of ‘chronic’ epilepsy? Epilepsia 1996 Aug; 37(8): 701–8

    Article  PubMed  CAS  Google Scholar 

  27. Musicco M, Beghi E, Solari A, et al. on behalf of the First Seizure Trial Group (FIRST Group). Treatment of first tonic-clonic seizure does not improve the prognosis of epilepsy. Neurology 1997 Oct; 49(4): 991–8

    Article  PubMed  CAS  Google Scholar 

  28. Perucca E, Gram L, Avanzini G, et al. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 1998 Jan; 39(1): 5–17

    Article  PubMed  CAS  Google Scholar 

  29. Perucca E. Pharmacological advantages of antiepileptic drug monotherapy. Epilepsia 1997; 38 Suppl. 5: 6S–8S

    Article  Google Scholar 

  30. Yuen AW, Land G, Weatherley B, et al. Sodium valproate acutely inhibits lamotrigine metabolism. Br J Clin Pharmacol 1992 May; 33(5): 511–3

    Article  PubMed  CAS  Google Scholar 

  31. Brodie MJ, Yuen AW, on behalf of the 105 Study Group. Lamotrigine substitution study: evidence for synergism with sodium valproate? Epilepsy Res 1997 Mar; 26(3): 423–32

    Article  PubMed  CAS  Google Scholar 

  32. 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 Aug; 40(8): 1141–6

    Article  PubMed  CAS  Google Scholar 

  33. Ferrie CD, Robinson RO, Knott C, et al. Lamotrigine as an add-on drug in typical absence seizures. Acta Neurol Scand 1995 Mar; 91(3): 200–2

    Article  PubMed  CAS  Google Scholar 

  34. Yukawa E. Optimisation of antiepileptic drug therapy: the importance of serum drug concentration monitoring. Clin Pharmacokinet 1996 Aug; 31(2): 120–30

    Article  PubMed  CAS  Google Scholar 

  35. Jannuzzi G, Cian P, Fattore C, et al. on behalf of The Italian TDM Study Group in Epilepsy. A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. Epilepsia 2000 Feb; 41(2): 222–30

    Article  PubMed  CAS  Google Scholar 

  36. Dulac O, Leppik IE. Initiating and discontinuing treatment. In: Engel Jr J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia (PA): Lippencott-Raven, 1997: 1237–46

    Google Scholar 

  37. Liu H, Delgado MR. A comprehensive study of the relation between serum concentrations, concentration ratios, and level/dose ratios of carbamazepine and its metabolites with age, weight, dose, and clearances in epileptic children. Epilepsia 1994 Nov-Dec; 35(6): 1221–9

    Article  PubMed  CAS  Google Scholar 

  38. Schachter SC. Antiepileptic drug therapy: general treatment principles and application for special patient populations. Epilepsia 1999; 40 Suppl. 9: 20S–5S

    Article  Google Scholar 

  39. Yerby MS, Friel PN, McCormick K. Antiepileptic drug disposition during pregnancy. Neurology 1992 Apr; 42(4 Suppl. 5): 12S–6S

    Google Scholar 

  40. Nau H, Zierer R, Spielmann H, et al. A new model for embryotoxicity testing: teratogenicity and pharmacokinetics of valproic acid following constant-rate administration in the mouse using human therapeutic drug and metabolite concentrations. Life Sci 1981 Dec 28; 29(26): 2803–14

    Article  PubMed  CAS  Google Scholar 

  41. Brodie MJ, Overstall PW, Giorgi L, on behalf of the UK Lamotrigine Elderly Study Group. Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. Epilepsy Res 1999 Oct; 37(1): 81–7

    Article  PubMed  CAS  Google Scholar 

  42. Kraemer G. Epilepsy in the elderly. Stuttgart: Thieme, 1999: 69–124

    Google Scholar 

  43. Holmes GL. Carbamazepine toxicity. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven Press, 1995: 567–79

    Google Scholar 

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Acknowledgements

Concepts presented in this manuscript were discussed in a workshop sponsored by UCB Pharma, Brussels, Belgium.

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Authors and Affiliations

  1. Clinical Pharmacology Unit, University of Pavia, Piazza Botta 10, 27100, Pavia, Italy

    Emilio Perucca

  2. Department of Pediatrics, Hôpital St-Vincent de Paul, Paris, France

    Olivier Dulac

  3. Institute of Neurology, University College London, Queen Square, London, England

    Simon Shorvon

  4. Department of Clinical Neuroscience, Division of Neurology, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden

    Torbjörn Tomson

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  1. Emilio Perucca
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  2. Olivier Dulac
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  3. Simon Shorvon
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  4. Torbjörn Tomson
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Correspondence to Emilio Perucca.

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Perucca, E., Dulac, O., Shorvon, S. et al. Harnessing the Clinical Potential of Antiepileptic Drug Therapy. CNS Drugs 15, 609–621 (2001). https://doi.org/10.2165/00023210-200115080-00004

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