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Pharmacokinetic interaction between retigabine and lamotrigine in healthy subjects

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The antiepileptic drugs (AEDs) retigabine (RGB) and lamotrigine (LTG) undergo predominantly N-glucuronidation and renal excretion. This study was performed to evaluate potential pharmacokinetic interactions between both AEDs.

Methods

Twenty-nine healthy male subjects participated in the study. Group A (n=14) received single oral 200-mg RGB doses on day 1 and day 7, and 25 mg o.i.d. LTG on days 3–8. Group B (n=15) received single oral 200-mg LTG doses on day 1 and day 17, and was up-titrated to 300 mg RGB b.i.d. on days 6–20. Blood samples were collected to compare the pharmacokinetics of both AEDs and the N-acetyl metabolite of RGB (AWD21–360) after single and concomitant treatments.

Results

RGB was rapidly absorbed and eliminated with a mean half-life (t1/2) of 6.3±1.1 h and an apparent clearance (CL/F) of 0.69±1.4 l/h/kg. Under co-administration of LTG, mean RGB t1/2 and area under the plasma concentration–time curve (AUC) were increased by 7.5% (P=0.045) and 15% (P=0.006), respectively, while CL/F was decreased by 13% (P=0.06). Consistent results were obtained for AWD21–360. LTG was moderately rapidly absorbed, eliminated with a mean t1/2 of 37±10.4 h and a CL/F of 0.028±0.007 l/h/kg. Under co-administration of RGB, mean LTG t1/2 and AUC decreased by 15% and 18%, respectively, while CL/F increased by 22% (all parameters, P=0.001).

Conclusions

RGB and LTG exhibit a modest pharmacokinetic interaction on each other. The slight decline in RGB clearance due to LTG is believed to result from competition for renal elimination rather than competition for glucuronidation. The induction of LTG clearance due to retigabine was unexpected since RGB did not show enzyme induction in various other drug–drug interaction studies. Further studies in patients are needed to assess the clinical relevance of these findings for concomitant treatment with both drugs in the upper recommended dose range.

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References

  1. Rundfeldt C, Netzer R (2000) The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary cells transfected with human KCNQ2/3 subunits. Neurosci Lett 281:73–76

    Article  Google Scholar 

  2. Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, Cohen US, Dixon JE, Mc Kinnon D (1998) KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282:1890–1893

    CAS  PubMed  Google Scholar 

  3. Main MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA et al (2000) Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Mol Pharmacol 58:253–262

    CAS  PubMed  Google Scholar 

  4. Wickenden AD, Yu WF, Zou A, Jegla T, Wagoner PK et al (2000) Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol Pharmacol 58:591–600

    CAS  PubMed  Google Scholar 

  5. Wickenden AD, Zou AR, Wagoner PK, Jegla T (2001) Characterization of KCNQ5/Q3 potassium channels expressed in mammalian cells. Br J Pharmacol 132:381–384

    CAS  PubMed  Google Scholar 

  6. Hirsch E, De Saint-Martin A, Marescaux C (1999) Benign neonatal familial convulsions: a model of idiopathic epilepsy. Rev Neurol (Paris) 155:463–467

    Google Scholar 

  7. Rundfeldt C, Netzer R (2000) Investigation into the mechanism of action of the new anticonvulsant retigabine: interaction with GABAergic and glutamatergic neuro-transmission and with voltage gated Na+ and Ca++ channels. Arzneimittelforschung 50:1063–1070

    CAS  PubMed  Google Scholar 

  8. Kapetanovic IM, Rundfeldt C (1996) A new anticonvulsant compound. CNS Drug Rev 2:308–321

    CAS  Google Scholar 

  9. Hermann R, Schneider E, Menth M, Knebel N, Ferron GM, Borlak J et al (2002) Retigabine. In: Bialer M et al (eds) Progress report on new antiepileptic drugs: a summary of the Sixth Eilat Conference (EILAT VI). Epilepsy Res 51:36–38

    Google Scholar 

  10. McNeilly PJ, Torchin CD, Anderson LW, Kapetanovic IM, Kupferberg HJ, Strong JM (1997) In vitro glucuronidation of D-23129, a new anticonvulsant, by human liver microsomes and liver slices. Xenobiotica 27:431–441

    CAS  PubMed  Google Scholar 

  11. Hiller A, Nguyen N, Strassburg CP, Li Q, Jainta H, Pechstein B et al (1999) Retigabine N-glucuronidation and its potential role in enterohepatic circulation. Drug Metab Dispos 27:605–612

    CAS  PubMed  Google Scholar 

  12. Ferron GM, Paul J, Fruncillo R, Richards L, Knebel NG, Getsy J et al (2002) Multiple-dose linear dose-proportional pharmacokinetics of retigabine in healthy volunteers. J Clin Pharm 42:175–182

    CAS  Google Scholar 

  13. Magdalou J, Herber R, Bidault R, Siest G (1992) In vitro N-glucuronidation of a novel antiepileptic drug, lamotrigine, by human liver microsomes. J Pharmacol Exp Ther 260:1166–1173

    CAS  PubMed  Google Scholar 

  14. Green MD, Tephly TR (1998) Glucuronidation of amine substrates by purified and expressed UDP–glucuronyltransferase proteins. Drug Metab Dispos 26:860–867

    CAS  PubMed  Google Scholar 

  15. Peck AW (1991) Clinical pharmacology of lamotrigine. Epilepsia 32:S9–S12

    PubMed  Google Scholar 

  16. Elwes RD, Binnie CD (1996) Clinical pharmacokinetics of newer antiepileptic drugs: lamotrigine, vigabatrin, gabapentin, and oxcarbazepine. Clin Pharmacokinet 30:403–415

    CAS  PubMed  Google Scholar 

  17. Rambeck B, Wolf P (1993) Lamotrigine clinical pharmacokinetics. Clin Pharmacokinet 25:433–443

    CAS  PubMed  Google Scholar 

  18. Richens A (1992) Pharmacokinetics of lamotrigine. In: Richens A (ed) Clinical update on lamotrigine: a novel entiepileptic agent. Wells Medical Ltd, Tunbridge Wells, pp 21–27

    Google Scholar 

  19. Yau MK, Adams MA, Wargin WA, Lai AA (1992) A single-dose and steady-state pharmacokinetic study of lamictal in healthy male volunteers. Third International Cleveland Clinic, Bethel Epilepsy Symposium, Cleveland, OH, USA

  20. Knebel NG, Grieb S, Leisenheimer S, Locher M (2000) Determination of retigabine and its acetyl metabolite in biological matrices by on-line solid-phase extraction (column switching) liquid chromatography with tandem mass spectrometry. J Chromatogr B Biomed Sci Appl 748:97–111

    Article  CAS  PubMed  Google Scholar 

  21. Sallustio BC, Morris RG (1997) High performance liquid chromatography quantitation of plasma lamotrigine concentrations: application measuring trough concentrations in patients with epilepsy. Ther Drug Monit 19:688–693

    Article  CAS  PubMed  Google Scholar 

  22. Lensmeyer GL, Gidal BE, Weibe DA (1997) Optimized high performance liquid chromatography method for determination of lamotrigine in serum with concomitant determination of phenytoin, carbamazepine and carbamazepine-epoxide. Ther Drug Monit 19:292–300

    Article  CAS  PubMed  Google Scholar 

  23. Rowland M, Tozer TN (1989) Clinical pharmacokinetics: concepts and applications, 2nd edn. Lea & Febiger, Philadelphia

    Google Scholar 

  24. Schuirmann D (1987) A comparison of the two one-sided test procedures and the power approach for assessing the equivalence of average bioavailability. J Pharm Biopharm 15:657–680

    CAS  Google Scholar 

  25. Committee for proprietary medicinal products (1995) Note for guidance on the investigation of drug interactions. CPMP/EWP/560/95

  26. Hussein Z, Posner J (1997) Population pharmacokinetics of lamotrigine monotherapy in patients with epilepsy: retrospective analysis of routine monitoring data. Br J Clin Pharmacol 43:457–465

    CAS  PubMed  Google Scholar 

  27. Ferron GM, Paul J, Richards L, Getsy J, Troy S (2001) Retigabine does not alter the pharmacokinetics of a low dose oral contraceptive in women. Neurology 56[Suppl 3]:P05.052

  28. Ferron GM, Patat A, Parks V, Troy S (2001) Lack of pharmacokinetic interaction between retigabine and phenobarbital at steady-state in healthy subjects. Clin Pharmacol Ther 69:48

    Article  PubMed  Google Scholar 

  29. Hermann R, Ferron GM, Erb K, Knebel N, Ruus P, Paul J, Richards L, Cnota HP, Troy S (2003) Effects of age and sex on the disposition of retigabine. Clin Pharmacol Ther 73:61–70

    Article  PubMed  Google Scholar 

  30. Potschka H, Fedrowitz M, Loscher W (2002) P-glycoprotein mediated efflux of phenobarbital, lamotrigine, and felbamate at the blood–brain barrier: evidence from microdialysis experiments in rats. Neurosci Lett 327:173–176

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The study was sponsored by ASTA Medica AG (predecessor of VIATRIS GmbH & Co. KG), Frankfurt am Main, Germany, and Wyeth Research, Philadelphia, USA.

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Authors and Affiliations

  1. Clinical Development, VIATRIS GmbH and Co. KG, Weismuellerstrasse 45, 60314 , Frankfurt am Main, Germany

    Robert Hermann

  2. Early Phase Development, VIATRIS GmbH and Co. KG, Frankfurt, Germany

    Norbert G. Knebel, Georg Niebch & Mathias Locher

  3. Wyeth-Ayerst Research, Philadelphia, PA, USA

    Lyette Richards

  4. Fraunhofer Institute of Toxicology, Drug Research and Clinical Inhalation, Center for Drug Research and Medical Biotechnology, Hannover, Germany

    Juergen Borlak

Authors
  1. Robert Hermann
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  2. Norbert G. Knebel
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  3. Georg Niebch
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  4. Lyette Richards
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  5. Juergen Borlak
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  6. Mathias Locher
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Correspondence to Robert Hermann.

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Hermann, R., Knebel, N.G., Niebch, G. et al. Pharmacokinetic interaction between retigabine and lamotrigine in healthy subjects. Eur J Clin Pharmacol 58, 795–802 (2003). https://doi.org/10.1007/s00228-003-0558-6

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  • DOI: https://doi.org/10.1007/s00228-003-0558-6

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