Skip to main content
SpringerLink
Log in

Effect of Lacosamide on the Steady-State Pharmacokinetics of Digoxin: Results from a Phase I, Multiple-Dose, Double-Blind, Randomised, Placebo-Controlled, Crossover Trial

  • Original Research Article
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Background

Recent data suggest that P-glycoprotein may be involved in cellular transport of lacosamide.

Objective

To investigate potential drug–drug interactions (DDIs) between lacosamide and digoxin, this phase I, multiple-dose, randomised, double-blind, placebo-controlled, crossover trial assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of digoxin administered in combination with lacosamide or placebo.

Methods

Twenty healthy White male volunteers were randomised. After receiving digoxin 0.25 mg three times daily on day 1 (loading dose), participants received digoxin 0.25 mg once daily on days 2–22. Participants received either lacosamide (200 mg twice daily) or placebo on days 8–11 and vice versa on days 18–21, after a 6-day washout. The steady-state area under concentration–time curve over the dosing interval (AUC24,ss) and maximum steady-state plasma concentration (C max,ss) of digoxin were measured; ratios of these parameters for co-administration of digoxin + lacosamide versus digoxin alone were used to evaluate potential DDIs. Interaction was excluded if the 90 % confidence interval (CI) for the geometric mean ratio of AUC24,ss and C max,ss fell within the acceptance range for bioequivalence (0.8–1.25).

Results

The point estimates (90 % CI) of the geometric mean ratios for co-administration of digoxin with lacosamide versus digoxin alone for AUC24,ss [1.024 (0.979–1.071)] and C max,ss [1.049 (0.959–1.147)] were within the acceptance range for bioequivalence. Digoxin and lacosamide co-administration was generally well-tolerated. A small numerical increase in the mean PR interval following co-administered digoxin + lacosamide was observed versus digoxin alone and versus pre-treatment baseline values (178.5 vs. 170.4 or 166.8 ms, respectively). The RR interval increased in parallel. The change was not considered clinically relevant.

Conclusion

Co-administration of steady-state digoxin (0.25 mg/day) with multiple-dose lacosamide (400 mg/day) versus digoxin alone revealed no differences in digoxin disposition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. UCB Pharma. Vimpat® (lacosamide) EPAR product information. Brussels, Belgium: UCB Pharma; 2012.

  2. UCB Inc. Vimpat® (lacosamide tablets, injection, oral solution. U.S. prescribing information. Smyrna, GA: UCB Inc; 2011.

  3. Sweetman SC, editor. Martindale: the complete drug reference. London: Pharmaceutical Press; 2002.

    Google Scholar 

  4. Terra SG, Washam JB, Dunham GD, et al. Therapeutic range of digoxin’s efficacy in heart failure: what is the evidence? Pharmacotherapy. 1999;19:1123–6.

    Article  CAS  PubMed  Google Scholar 

  5. Rodin SM, Johnson BF. Pharmacokinetic interactions with digoxin. Clin Pharmacokinet. 1988;15:227–44.

    Article  CAS  PubMed  Google Scholar 

  6. Cheng S, Keyes MJ, Larson MG, et al. Long-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular block. JAMA. 2009;301:2571–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Beyreuther BK, Freitag J, Heers C, et al. Lacosamide: a review of preclinical properties. CNS Drug Rev. 2007;13:21–42.

    Article  CAS  PubMed  Google Scholar 

  8. Cawello W, Boekens H, Bonn R. Absorption, disposition, metabolic fate and elimination of the anti-epileptic drug lacosamide in humans: mass balance following intravenous and oral administration. Eur J Drug Metab Pharmacokinet. 2012;37:241–8.

    Article  CAS  PubMed  Google Scholar 

  9. Cawello W, Bonn R, Boekens H. Bioequivalence of intravenous and oral formulations of the antiepileptic drug lacosamide. Pharmacology. 2012;90:40–6.

    Article  CAS  PubMed  Google Scholar 

  10. 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;61:1–48.

    Article  PubMed  Google Scholar 

  11. Horstmann R, Bonn R, Cawello W, et al. Basic clinical pharmacological investigations of the new antiepileptic drug SPM 927 [abstract]. Epilepsia. 2002;43(suppl 7):188.

    Google Scholar 

  12. Cawello W, Bökens O, Nickel B, et al. Tolerability, pharmacokinetics, and bioequivalence of the tablet and syrup formulations of lacosamide in plasma, saliva, and urine: saliva as a surrogate of pharmacokinetics in the central compartment. Epilepsia. 2013;54:81–8.

    Article  CAS  PubMed  Google Scholar 

  13. Fountain N, Staelens L, Tytgat D, et al. Low lacosamide plasma protein binding in lacosamide-naive patients [abstract no. P01.077]. Neurology. 2012;78(P01):077.

    Google Scholar 

  14. Cawello W, Nickel B, Zisowsky J, et al. Population pharmacokinetics of the new antiepileptic drug lacosamide in subjects with diabetic neuropathic pain [abstract]. J Clin Pharmacol. 2008;48:1133.

    Google Scholar 

  15. Nickel B, Zisowsky J, Cawello W, et al. Population pharmacokinetics of lacosamide in subjects with partial-onset seizures: results from two phase III trials [abstract]. J Clin Pharmacol. 2008;48:1129.

    Google Scholar 

  16. Schiltmeyer B, Cawello W, Kropeit D, et al. Population pharmacokinetics of the new antiepileptic drug lacosamide in healthy subjects with different age and gender. Population Approach Group in Europe (PAGE); 16-17 Jun 2005; Pamplona.

  17. Iisalo E. Clinical pharmacokinetics of digoxin. Clin Pharmacokinet. 1977;2:1–16.

    Article  CAS  PubMed  Google Scholar 

  18. Aronson JK. Clinical pharmacokinetics of digoxin 1980. Clin Pharmacokinet. 1980;5:137–49.

    Article  CAS  PubMed  Google Scholar 

  19. Keller F, Blumenthal HP, Maertin K, et al. Overall pharmacokinetics during prolonged treatment of healthy volunteers with digoxin and beta-methyldigoxin. Eur J Clin Pharmacol. 1977;12:387–92.

    Article  CAS  PubMed  Google Scholar 

  20. Greenwood H, Snedden W, Hayward RP, et al. The measurement of urinary digoxin and dihydrodigoxin by radioimmunoassay and by mass spectroscopy. Clin Chim Acta. 1975;62:213–24.

    Article  CAS  PubMed  Google Scholar 

  21. GlaxoSmithKline. Lanoxin (digoxin) injection pediatric [NDA 09330/S-025] 2009 August, 2009. http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/009330s025lbl.pdf. Accessed 30 Sep 2013

  22. Lacarelle B, Rahmani R, de Sousa G, et al. Metabolism of digoxin, digoxigenin digitoxosides and digoxigenin in human hepatocytes and liver microsomes. Fundam Clin Pharmacol. 1991;5:567–82.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang C, Chanteux H, Zuo Z, et al. Potential role for human P-glycoprotein in the transport of lacosamide. Epilepsia. 2013;54:1154–60.

    Article  CAS  PubMed  Google Scholar 

  24. US Food and Drug Administration (FDA). Guidance for industry: bioavailability and bioequivalence studies for orally administered drug products—general considerations. Rockville: Center for Drug Evaluation and Research; 2003.

  25. European Agency for the Evaluation of Medicinal Products. The European Agency for the evaluation of medicinal products, Committee for Proprietary Medicinal Products (CPMP). Note for guidance on the investigation of bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98). London: CPMP; 2001. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003008.pdf. Cited 18 Feb 2014.

  26. Cawello W, Bonn R. No pharmacokinetic interaction between lacosamide and valproic acid in healthy volunteers. J Clin Pharmacol. 2012;52:1739–48.

    Article  CAS  PubMed  Google Scholar 

  27. Cawello W, Nickel B, Eggert-Formella A. No pharmacokinetic interaction between lacosamide and carbamazepine in healthy volunteers. J Clin Pharmacol. 2010;50:459–71.

    Article  CAS  PubMed  Google Scholar 

  28. Thomas D, Scharfenecker U, Nickel B, et al. Lacosamide has low potential for drug–drug interaction [abstract no. T232]. Epilepsia. 2008;50:110.

    Google Scholar 

  29. Cawello W, Rosenkranz B, Schmid B, et al. Pharmacodynamic and pharmacokinetic evaluation of coadministration of lacosamide and an oral contraceptive (levonorgestrel plus ethinylestradiol) in healthy female volunteers. Epilepsia. 2013;54:530–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr. Hartmut Dietrich, MD of ClinPharmCologne TROPON GmbH for serving as the principle investigator for this trial and Dr. Klaus Eckhardt, MD of UCB Pharma for his helpful contributions. Dr. Dietrich did not participate in the drafting and approval of this manuscript and therefore did not meet ICMJE authorship criteria. Apurva Davé, PhD of Prescott Medical Communications Group (Chicago, IL, USA) provided writing and editorial support, which was funded by UCB Pharma. Editorial support was also provided by Karen Burrows, MPhil, of Evidence Scientific Solutions (Horsham, UK), which was funded by UCB Pharma.

Financial Disclosure

UCB Pharma (Monheim, Germany) provided the trial supplies and sponsored and funded the trial. The authors are employees of UCB Biosciences GmbH (part of UCB Pharma).

Author information

Authors and Affiliations

  1. UCB Biosciences GmbH, UCB Pharma, Global Statistical Sciences, Alfred-Nobel-Str. 10, 40789, Monheim am Rhein, Germany

    Willi Cawello & Jens-Otto Andreas

  2. UCB Biosciences GmbH, UCB Pharma, Clinical QA, Alfred-Nobel-Str. 10, 40789, Monheim am Rhein, Germany

    Christa Mueller-Voessing

Authors
  1. Willi Cawello
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christa Mueller-Voessing
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jens-Otto Andreas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Willi Cawello.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cawello, W., Mueller-Voessing, C. & Andreas, JO. Effect of Lacosamide on the Steady-State Pharmacokinetics of Digoxin: Results from a Phase I, Multiple-Dose, Double-Blind, Randomised, Placebo-Controlled, Crossover Trial. Clin Drug Investig 34, 327–334 (2014). https://doi.org/10.1007/s40261-014-0180-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-014-0180-7

Keywords

Search

Navigation