Clinical Pharmacokinetics

, Volume 43, Issue 11, pp 707–724 | Cite as

Clinical Pharmacokinetics of Levetiracetam

Review Article

Abstract

Since 1989, eight new antiepileptic drugs (AEDs) have been licensed for clinical use. Levetiracetam is the latest to be licensed and is used as adjunctive therapy for the treatment of adult patients with partial seizures with or without secondary generalisation that are refractory to other established first-line AEDs.

Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. After oral ingestion, levetiracetam is rapidly absorbed, with peak concentration occurring after 1.3 hours, and its bioavailability is ≥95%. Co-ingestion of food slows the rate but not the extent of absorption. Levetiracetam is not bound to plasma proteins and has a volume of distribution of 00.5–0.7 L/kg. Plasma concentrations increase in proportion to dose over the clinically relevant dose range (500–5000mg) and there is no evidence of accumulation during multiple administration. Steady-state blood concentrations are achieved within 24–48 hours.

The elimination half-life in adult volunteers, adults with epilepsy, children with epilepsy and elderly volunteers is 6–8, 6–8, 5–7 and 10–11 hours, respectively. Approximately 34% of a levetiracetam dose is metabolised and 66% is excreted in urine unmetabolised; however, the metabolism is not hepatic but occurs primarily in blood by hydrolysis. Autoinduction is not a feature. As clearance is renal in nature it is directly dependent on creatinine clearance. Consequently, dosage adjustments are necessary for patients with moderate to severe renal impairment.

To date, no clinically relevant pharmacokinetic interactions between AEDs and levetiracetam have been identified. Similarly, levetiracetam does not interact with digoxin, warfarin and the low-dose contraceptive pill; however, adverse pharmacodynamic interactions with carbamazepine and topiramate have been demonstrated. Overall, the pharmacokinetic characteristics of levetiracetam are highly favourable and make its clinical use simple and straightforward.

Keywords

Carbamazepine Valproic Acid Lamotrigine Topiramate Levetiracetam 

Notes

Acknowledgements

The work of the author is supported by the National Society for Epilepsy, University College Hospitals NHS Trust and the Institute of Neurology, University College, London. The author has no conflict of interest directly relevant to the content of this review.

References

  1. 1.
    Sander JW, Shorvon SD. Epidemiology of the epilepsies. J Neurol Neurosurg Psychiatry 1996; 61: 433–43PubMedCrossRefGoogle Scholar
  2. 2.
    Patsalos PN, Froscher W, Pisani F, et al. The importance of drug interactions in epilepsy therapy. Epilepsia 2002; 43: 365–85PubMedCrossRefGoogle Scholar
  3. 3.
    Walker MC, Patsalos PN. Clinical pharmacokinetics of new antiepileptic drugs. Pharmacol Ther 1995; 67: 351–84PubMedCrossRefGoogle Scholar
  4. 4.
    Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000; 85: 77–85PubMedCrossRefGoogle Scholar
  5. 5.
    Patsalos PN. The new generation of anti-epileptic drugs. In: Bowman WC, Fitzgerald JD, Taylor JB, editors. Emerging drugs: the prospect for improved medicines. Vol. 4. London: Ashley Publications Ltd, 1999: 87–106Google Scholar
  6. 6.
    Cereghino J, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology 2000; 55: 236–42PubMedCrossRefGoogle Scholar
  7. 7.
    Betts T, Waegemans T, Crawford P. A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000mg daily and 4000mg daily, without titration in patients with refractory epilepsy. Seizure 2000; 9: 80–7PubMedCrossRefGoogle Scholar
  8. 8.
    Krauss GL, Abou-Khalil B, Sheth SG, et al. Efficacy of levetiracetam for treatment of drug-resistant generalized epilepsy [abstract]. Epilepsia 2001; 42 Suppl. 7: 181Google Scholar
  9. 9.
    French J, Edrich P, Cramer JA. A systematic review of the safety profile of levetiracetam: a new antiepileptic drug. Epilepsy Res 2001; 47: 77–90PubMedCrossRefGoogle Scholar
  10. 10.
    Klitgaard H, Matagne A, Gobert J, et al. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. Eur J Pharmacol 1988; 353: 191–206CrossRefGoogle Scholar
  11. 11.
    Löscher W, Hönack D, Rundfeldt C. Antiepileptogenic effects of the novel anticonvulsant levetiracetam (UCB L059) in the kindling model of temporal lobe epilepsy. J Pharmacol Exp Ther 1998; 284: 474–9PubMedGoogle Scholar
  12. 12.
    Mitchell TN, Sander JW. Levetiracetam: a new antiepileptic drug for adjunctive therapy of chronic epilepsy. Drugs Today 2001; 37: 665–73PubMedCrossRefGoogle Scholar
  13. 13.
    Shorvon SD. Pyrrolidone derivatives. Lancet 2001; 358: 1885–92PubMedCrossRefGoogle Scholar
  14. 14.
    Vermeij TAC, Edelbroek PM. High-performance liquid chromatographic and megabore gas-liquid chromatographic determination of levetiracetam (UCB L059) in human serum after solid-phase extraction. J Chromatogr Biomed Appl 1994; 662: 134–9CrossRefGoogle Scholar
  15. 15.
    Ratnaraj N, Doheny HC, Patsalos PN. A micromethod for the determination of the new antiepileptic drug levetiracetam (UCB LO59) in serum or plasma by high performance liquid chromatography. Ther Drug Monit 1996; 18: 154–7PubMedCrossRefGoogle Scholar
  16. 16.
    Coupez R, Nicolas JM, Browne TR. Levetiracetam, a new antiepileptic agent: lack of in vitro and in vivo pharmacokinetic interaction with valproic acid. Epilepsia 2003; 44: 171–8PubMedCrossRefGoogle Scholar
  17. 17.
    Pucci V, Bugamelli F, Mandrioli R, et al. High-performance liquid chromatographic determination of levetiracetam in human plasma: comparison of different sample clean-up procedures. Biomed Chromatogr 2004; 18: 37–44PubMedCrossRefGoogle Scholar
  18. 18.
    Isoherränen N, Roeder M, Soback S, et al. Enantioselective analysis of levetiracetam and its enantiomers R-alphaethyl-2-oxo-pyrrolidine acetamide using gas chromatography and ion trap mass spectrometric detection. J Chromatogr B 2000; 745: 325–32CrossRefGoogle Scholar
  19. 19.
    Ivanova M, Piunti A, Marziali E. et al. Microemulsion electrokinetic chromatography applied for separation of levetiracetam from other entiepileptic drugs in polypharmacy. Electrophoresis 2003; 24: 992–8PubMedCrossRefGoogle Scholar
  20. 20.
    Shihabi ZK, Oles K, Hinsdale M. Analysis of the antiepileptic drug keppra by cappillary electrophoresis. J Chromatogr A 2003; 1004: 9–12PubMedCrossRefGoogle Scholar
  21. 21.
    Trinka E, Unterrainer J, Unterberger I, et al. One-year postmarketing experience with levetiracetam for treatment of drug-resistant epilepsy: a cross-sectional study [abstract]. Epilepsia 2002; 43 Suppl. 7: 202Google Scholar
  22. 22.
    Perucca E, Gidal BE, Bates E. Effects of antiepileptic comedication on levetiracetam pharmacokinetics: a pooled analysis of data from randomised adjunctive trials. Epilepsy Res 2003; 53: 47–56PubMedCrossRefGoogle Scholar
  23. 23.
    Gidal BE, Sheth RD, Hutson PR, et al. Oral absorption kinetics of levetiracetam: effect of mixing with foods or enteral nutrition formulas [abstract]. Epilepsia 2003; 44 Suppl. 9: 99Google Scholar
  24. 24.
    Edwards KR, Glantz MJ, Bator T, et al. Levetiracetam levels in human cerebrospinal fluid: a controlled, dose ranging pharmacokinetic study [abstract]. Neurology 2004; 62 Suppl 5: A118Google Scholar
  25. 25.
    Doheny HC, Ratnaraj N, Whittington MA, et al. Blood and cerebrospinal fluid pharmacokinetics of the novel anticonvulsant levetiracetam (UCB L059) in the rat. Epilepsy Res 1999; 34: 161–8PubMedCrossRefGoogle Scholar
  26. 26.
    Tong X, Patsalos PN. A microdialysis study of the novel antiepileptic drug levetiracetam: extracellular pharmacokinetics and effect on taurine in rat brain. Br J Pharmacol 2002; 133: 867–74CrossRefGoogle Scholar
  27. 27.
    Potschka H, Baltes S, Loscher W. Inhibition of multidrug transporters by verapamil or probenecid does not alter blood-brain barrier penetration of levetiracetam in rats. Epilepsy Res 2004; 58: 85–91PubMedCrossRefGoogle Scholar
  28. 28.
    Kramer G, Hosli I, Glanzmann R, et al. Levetiracetam accumulation in human breast milk [abstract]. Epilepsia 2002; 43 Suppl. 7: 105Google Scholar
  29. 29.
    Strolin Benedetti M, Whomsley R, Nicolas JM, et al. Pharmacokinetics and metabolism of 14 C-levetiracetam, a new antiepileptic agent, in healthy volunteers. Eur J Clin Pharmacol 2003; 59: 621–30PubMedCrossRefGoogle Scholar
  30. 30.
    Isoherränen N, Yagen B, Soback S, et al. Pharmacokinetics of levetiracetam and its enantiomer (R)-α-ethyl-2-oxo-pyrrolidine acetamide in dogs. Epilepsia 2001; 42: 825–30PubMedCrossRefGoogle Scholar
  31. 31.
    Slatter J, Su P, Sams J, et al. Bioactivation of the anticancer agent CPT-11 to SN-38 by human hepatic microsomal carboxylases and the in vitro assessment of potential interaction. Drug Metab Dispos 1997; 25: 1157–64PubMedGoogle Scholar
  32. 32.
    Patsalos PN, Doheny HC. Blood and cerebrospinal fluid kinetics of carbamazepine and levetiracetam during long-term administration to rats: carbamazepine but not levetiracetam exhibits autoinduction [abstract]. Epilepsia 2002; 43 Suppl. 7: 220Google Scholar
  33. 33.
    Pellock JM, Glauser TA, Bebin EM, et al. Pharmacokinetic study of levetiracetam in children. Epilepsia 2001; 42: 1574–9PubMedCrossRefGoogle Scholar
  34. 34.
    Baltez E, Coupez R. Levetiracetam dose adjustment for patients on hemodialysis [abstract]. Epilepsia 2000; 41 Suppl. 7: 254Google Scholar
  35. 35.
    Brockmoller J, Thomsen T, Eckl K, et al. Levetiracetam: liver impairment does not influence its pharmacokinetic profile [abstract]. Epilepsia 2000; 41 Suppl.: 150Google Scholar
  36. 36.
    Patsalos PN. Phenobarbitone to gabapentin: a guide to 82 years of anti-epileptic drug pharmacokinetic interactions. Seizure 1994; 3: 163–70PubMedCrossRefGoogle Scholar
  37. 37.
    Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurology 2003; 2: 347–56PubMedCrossRefGoogle Scholar
  38. 38.
    Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurology 2003; 2: 473–81PubMedCrossRefGoogle Scholar
  39. 39.
    Nicolas JM, Collart P, Gerin B, et al. In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent. Drug Metab Dispos 1999; 27: 250–4PubMedGoogle Scholar
  40. 40.
    Levy RH, Ragueneau-Majlessi I, Baltes E. Repeated administration of the novel antiepileptic agent levetiracetam does not alter digoxin pharmacokinetics and pharmacodynamics in healthy volunteers. Epilepsy Res 2001; 46: 93–9PubMedCrossRefGoogle Scholar
  41. 41.
    Ragueneau-Majlessi I, Levy RH, Meyerhoff C. Lack of effect of repeated administration of levetiracetam on the pharmacodynamic and pharmacokinetic profiles of warfarin. Epilepsy Res 2001; 47: 55–63PubMedCrossRefGoogle Scholar
  42. 42.
    Ragueneau-Majlessi I, Levy RH, Janik F. Levetiracetam does not alter the pharmacokinetics of an oral contraceptive in healthy volunteers. Epilepsia 2002; 43: 697–702PubMedCrossRefGoogle Scholar
  43. 43.
    Radtke RA. Pharmacokinetics of levetiracetam. Epilepsia 2001; 42 Suppl. 4: 24–7PubMedCrossRefGoogle Scholar
  44. 44.
    Sharief MK, Singh P, Sander JWAS, et al. Efficacy and tolerability study of UCB L059 in patients with refractory epilepsy. J Epilepsy 1996; 9: 106–12CrossRefGoogle Scholar
  45. 45.
    Ben-Menachem E, Falteru U. Efficacy and tolerability of levetiracetam 3000 mg/day in patients with refractory partial seizures: a multicentre, double-blind, responder-selected study evaluating monotherapy. Epilepsia 2000; 41: 1276–83PubMedCrossRefGoogle Scholar
  46. 46.
    Grant R, Shorvon SD. Efficacy and tolerability of 1000–4000mg per day of levetiracetam as add-on therapy in patients with refractory epilepsy. Epilepsy Res 2000; 42: 89–95PubMedCrossRefGoogle Scholar
  47. 47.
    Shorvon SD, Lowenthal A, Janz D, et al. Multicentre doubleblind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia 2000; 41: 1179–86PubMedCrossRefGoogle Scholar
  48. 48.
    Boon P, Chauvel P, Pohlmann-Eden B, et al. Dose-response effect of levetiracetam 1000 and 2000 mg/day partial epilepsy. Epilepsy Res 2002; 48: 77–89PubMedCrossRefGoogle Scholar
  49. 49.
    Perucca E, Baltes E, Ledent E. Levetiracetam: absence of pharmacokinetic interactions with other antiepileptic drugs (AEDs) [abstract]. Epilepsia 2000; 41 Suppl.: 150Google Scholar
  50. 50.
    Glauser TA, Pellock JM, Bebin EM, et al. Efficacy and safety of levetiracetam in children with partial seizures: an open-label trial. Epilepsia 2002; 43: 518–24PubMedCrossRefGoogle Scholar
  51. 51.
    Kasteleijn-Nolst Trenite DGA, Marescaux C, Stodieck S, et al. Photosensitive epilepsy: a model to study the effects of antiepileptic drugs: evaluation of the piracetam analogue, levetiracetam. Epilepsy Res 1996; 25: 225–30PubMedCrossRefGoogle Scholar
  52. 52.
    May TW, Rambeck B, Jurgens U. Serum concentrations of levetiracetam in epileptic patients: the influence of dose and co-medication. Ther Drug Monit 2003; 25: 690–9PubMedCrossRefGoogle Scholar
  53. 53.
    Browne TR, Szabo GK, Leppik IE, et al. Absence of pharmacokinetic drug interaction of levetiracetam with phenytoin in patients with epilepsy determined by new technique. J Clin Pharmacol 2000; 40: 590–5PubMedCrossRefGoogle Scholar
  54. 54.
    Klitgaard H, Matagne A. Levetiracetam enhances markedly the seizure suppression of other antiepileptic drugs in amygdala-kindled rats [abstract]. Epilepsia 2002; 43 Suppl. 7: 219Google Scholar
  55. 55.
    Matagne AC, Baltes E, Coupez R, et al. Levetiracetam enhances markedly the seizure suppression of other antiepileptic drugs in audiogenic susceptible mice [abstract]. Epilepsia 2001; 42 Suppl 7: 82Google Scholar
  56. 56.
    Matagne AC, Baltes E, Coupe R, et al. Levetiracetam in combination with other antiepileptic drugs shows enhanced antiepileptic activity in animal models [abstract]. Eur J Neurol 2002; 9 Suppl. 2: 179CrossRefGoogle Scholar
  57. 57.
    Wasterlain C, Mazarati AM, Klitgaard H, et al. Synergistic action of levetiracetam and diazepam in the treatment of experimental status epilepticus [abstract]. Epilepsia 2002; 43 Suppl. 8: 60Google Scholar
  58. 58.
    Sisodiya SM, Sander JWAS, Patsalos PN. Carbamazepine toxicity during combination therapy with levetiracetam: a pharmacodynamic interaction. Epilepsy Res 2002; 48: 217–9PubMedCrossRefGoogle Scholar
  59. 59.
    Johannessen SI, Battino D, Berry DJ, et al. Therapeutic drug monitoring of the newer antiepileptic drugs. Ther Drug Monit 2003; 25: 347–63PubMedCrossRefGoogle Scholar
  60. 60.
    Folland C, Moriarty GL. Clinical experience of levetiracetam (LEV) in refractory adult epilepsy patients [abstract]. Epilepsia 2002; 43 Suppl. 7: 192Google Scholar
  61. 61.
    Mushtaq R, Wannamaker BB. Levetiracetam blood levels have utility in clinical management of epilepsy [abstract]. Epilepsia 2002; 43 Suppl. 7: 107Google Scholar
  62. 62.
    Lindholm D. Levetiracetam levels correlating with successful treatment of epilepsy, headaches, cognitive effects, and adverse reactions in pediatric age group [abstract]. Epilepsia 2002; 43 Suppl. 7: 60Google Scholar
  63. 63.
    Liu H, Delgado MR. Therapeutic drug concentration monitoring using saliva samples: focus on anticonvulsants. Clin Pharmacokinet 1999; 36: 453–70PubMedCrossRefGoogle Scholar
  64. 64.
    Gorodischer R, Burtin P, Hwang P, et al. Saliva versus blood sampling for therapeutic drug monitoring in children: patient and parental preferences and an economic analysis. Ther Drug Monit 1994; 16: 437–43PubMedCrossRefGoogle Scholar
  65. 65.
    Drobitch RK, Svensson CK. Therapeutic drug monitoring in saliva: an update. Clin Pharmacokinet 1992; 23: 365–79PubMedCrossRefGoogle Scholar
  66. 66.
    Cardot JM, Degen P, Flesch G, et al. Comparison of plasma and saliva concentrations of the active monohydroxy metabolite of oxcarbazepine in patients at steady state. Biopharm Drug Dispos 1995; 16: 603–14PubMedCrossRefGoogle Scholar
  67. 67.
    Klitgaard NA, Kristensen O. Use of saliva for monitoring oxcarbazepine therapy in epileptic patients. Eur J Clin Pharmacol 1986; 31: 91–4PubMedCrossRefGoogle Scholar
  68. 68.
    Kumagai N, Seki T, Yamada T, et al. Concentrations of zonisamide in serum, free fraction, mixed saliva and cerebrospinal fluid in epileptic children treated with monotherapy. Jpn J Psychol Neurol 1993; 47: 291–2Google Scholar
  69. 69.
    Tsiropoulos I, Kristensen O, Klitgaard NA. Saliva and serum concentrations of lamotrigine in patients with epilepsy. Ther Drug Monit 2000; 22: 517–21PubMedCrossRefGoogle Scholar
  70. 70.
    Grim SA, Ryan M, Miles MV, et al. Correlation of levetiracetam concentrations between serum and saliva. Ther Drug Monit 2003; 25: 61–6PubMedCrossRefGoogle Scholar
  71. 71.
    Kossoff EH, Bergey GK, Freeman JM, et al. Levetiracetam psychosis in children with epilepsy. Epilepsia 2001; 42: 1611–3PubMedCrossRefGoogle Scholar
  72. 72.
    Wheless JW, Ng YT. Levetiracetam in refractory pediatric epilepsy. J Clin Neurol 2002; 17: 413–5Google Scholar
  73. 73.
    Sohn YH, Kaelin-Lang A, Jung HY, et al. Effect of levetiracetam on human corticospinal excitability. Neurology 2001; 57: 858–63PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Pharmacology and Therapeutics Unit, Department of Clinical and Experimental EpilepsyInstitute of Neurology/The National Hospital for Neurology and NeurosurgeryLondonUK
  2. 2.The National Society for EpilepsyChalfont Centre for EpilepsyChalfont St PeterUK

Personalised recommendations