nach oben

Clinical Pharmacokinetics

Erschienen in:

01.09.2004 | Review Article

Clinical Pharmacokinetics of Levetiracetam

verfasst von: Prof. Philip N. Patsalos

Erschienen in: Clinical Pharmacokinetics | Ausgabe 11/2004

Einloggen, um Zugang zu erhalten

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.

The use of trade names is for product identification purposes only and does not imply endorsement.

Sander JW, Shorvon SD. Epidemiology of the epilepsies. J Neurol Neurosurg Psychiatry 1996; 61: 433–43PubMedCrossRef

Patsalos PN, Froscher W, Pisani F, et al. The importance of drug interactions in epilepsy therapy. Epilepsia 2002; 43: 365–85PubMedCrossRef

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

Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000; 85: 77–85PubMedCrossRef

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: 87–106

Cereghino J, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology 2000; 55: 236–42PubMedCrossRef

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: 80–7PubMedCrossRef

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: 181

French J, Edrich P, Cramer JA. A systematic review of the safety profile of levetiracetam: a new antiepileptic drug. Epilepsy Res 2001; 47: 77–90PubMedCrossRef

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: 191–206CrossRef

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: 474–9PubMed

12.

Mitchell TN, Sander JW. Levetiracetam: a new antiepileptic drug for adjunctive therapy of chronic epilepsy. Drugs Today 2001; 37: 665–73PubMedCrossRef

13.

Shorvon SD. Pyrrolidone derivatives. Lancet 2001; 358: 1885–92PubMedCrossRef

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: 134–9CrossRef

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: 154–7PubMedCrossRef

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: 171–8PubMedCrossRef

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: 37–44PubMedCrossRef

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: 325–32CrossRef

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: 992–8PubMedCrossRef

20.

Shihabi ZK, Oles K, Hinsdale M. Analysis of the antiepileptic drug keppra by cappillary electrophoresis. J Chromatogr A 2003; 1004: 9–12PubMedCrossRef

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: 202

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: 47–56PubMedCrossRef

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: 99

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: A118

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: 161–8PubMedCrossRef

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: 867–74CrossRef

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: 85–91PubMedCrossRef

28.

Kramer G, Hosli I, Glanzmann R, et al. Levetiracetam accumulation in human breast milk [abstract]. Epilepsia 2002; 43 Suppl. 7: 105

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: 621–30PubMedCrossRef

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: 825–30PubMedCrossRef

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: 1157–64PubMed

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: 220

33.

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

34.

Baltez E, Coupez R. Levetiracetam dose adjustment for patients on hemodialysis [abstract]. Epilepsia 2000; 41 Suppl. 7: 254

35.

Brockmoller J, Thomsen T, Eckl K, et al. Levetiracetam: liver impairment does not influence its pharmacokinetic profile [abstract]. Epilepsia 2000; 41 Suppl.: 150

36.

Patsalos PN. Phenobarbitone to gabapentin: a guide to 82 years of anti-epileptic drug pharmacokinetic interactions. Seizure 1994; 3: 163–70PubMedCrossRef

37.

Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurology 2003; 2: 347–56PubMedCrossRef

38.

Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: interactions between antiepileptic drugs and other drugs. Lancet Neurology 2003; 2: 473–81PubMedCrossRef

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: 250–4PubMed

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: 93–9PubMedCrossRef

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: 55–63PubMedCrossRef

42.

Ragueneau-Majlessi I, Levy RH, Janik F. Levetiracetam does not alter the pharmacokinetics of an oral contraceptive in healthy volunteers. Epilepsia 2002; 43: 697–702PubMedCrossRef

43.

Radtke RA. Pharmacokinetics of levetiracetam. Epilepsia 2001; 42 Suppl. 4: 24–7PubMedCrossRef

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: 106–12CrossRef

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: 1276–83PubMedCrossRef

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: 89–95PubMedCrossRef

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: 1179–86PubMedCrossRef

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: 77–89PubMedCrossRef

49.

Perucca E, Baltes E, Ledent E. Levetiracetam: absence of pharmacokinetic interactions with other antiepileptic drugs (AEDs) [abstract]. Epilepsia 2000; 41 Suppl.: 150

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: 518–24PubMedCrossRef

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: 225–30PubMedCrossRef

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: 690–9PubMedCrossRef

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: 590–5PubMedCrossRef

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: 219

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: 82

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: 179CrossRef

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: 60

58.

Sisodiya SM, Sander JWAS, Patsalos PN. Carbamazepine toxicity during combination therapy with levetiracetam: a pharmacodynamic interaction. Epilepsy Res 2002; 48: 217–9PubMedCrossRef

59.

Johannessen SI, Battino D, Berry DJ, et al. Therapeutic drug monitoring of the newer antiepileptic drugs. Ther Drug Monit 2003; 25: 347–63PubMedCrossRef

60.

Folland C, Moriarty GL. Clinical experience of levetiracetam (LEV) in refractory adult epilepsy patients [abstract]. Epilepsia 2002; 43 Suppl. 7: 192

61.

Mushtaq R, Wannamaker BB. Levetiracetam blood levels have utility in clinical management of epilepsy [abstract]. Epilepsia 2002; 43 Suppl. 7: 107

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: 60

63.

Liu H, Delgado MR. Therapeutic drug concentration monitoring using saliva samples: focus on anticonvulsants. Clin Pharmacokinet 1999; 36: 453–70PubMedCrossRef

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: 437–43PubMedCrossRef

65.

Drobitch RK, Svensson CK. Therapeutic drug monitoring in saliva: an update. Clin Pharmacokinet 1992; 23: 365–79PubMedCrossRef

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: 603–14PubMedCrossRef

67.

Klitgaard NA, Kristensen O. Use of saliva for monitoring oxcarbazepine therapy in epileptic patients. Eur J Clin Pharmacol 1986; 31: 91–4PubMedCrossRef

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: 291–2

69.

Tsiropoulos I, Kristensen O, Klitgaard NA. Saliva and serum concentrations of lamotrigine in patients with epilepsy. Ther Drug Monit 2000; 22: 517–21PubMedCrossRef

70.

Grim SA, Ryan M, Miles MV, et al. Correlation of levetiracetam concentrations between serum and saliva. Ther Drug Monit 2003; 25: 61–6PubMedCrossRef

71.

Kossoff EH, Bergey GK, Freeman JM, et al. Levetiracetam psychosis in children with epilepsy. Epilepsia 2001; 42: 1611–3PubMedCrossRef

72.

Wheless JW, Ng YT. Levetiracetam in refractory pediatric epilepsy. J Clin Neurol 2002; 17: 413–5

73.

Sohn YH, Kaelin-Lang A, Jung HY, et al. Effect of levetiracetam on human corticospinal excitability. Neurology 2001; 57: 858–63PubMedCrossRef

Titel: Clinical Pharmacokinetics of Levetiracetam
verfasst von: Prof. Philip N. Patsalos
Publikationsdatum: 01.09.2004
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 11/2004
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.2165/00003088-200443110-00002

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 11/2004

Risperidone Does Not Affect Steady-State Pharmacokinetics of Divalproex Sodium in Patients with Bipolar Disorder

Time-Related Clinical Determinants of Long-Term Tacrolimus Pharmacokinetics in Combination Therapy with Mycophenolic Acid and Corticosteroids

Potential Role of Cerebral Cytochrome P450 in Clinical Pharmacokinetics

Effect of Rifampicin on the Pharmacokinetics of Fluconazole in Patients with AIDS