Clinical Rheumatology

, Volume 32, Issue 2, pp 267–270 | Cite as

Leflunomide in dialysis patients with rheumatoid arthritis—a pharmacokinetic study

  • Raoul Bergner
  • Lena Peters
  • Verena Schmitt
  • Christian Löffler
Brief Report

Abstract

Pharmacokinetic data of disease modifying antirheumatic drugs during hemodialysis are limited to sulfasalazine, methotrexate, and cyclosporine. Only respective anecdotal data have been reported on leflunomide. We repeatedly measured teriflunomide (A77-1726), the active metabolite of leflunomide, during standard hemodialysis sessions and calculated teriflunomide clearances in five patients with rheumatoid arthritis (RA) and end-stage renal disease. The calculated teriflunomide clearances during a standardized dialysis session of 3–4.5 h at a blood flow rate of 160–300 ml/min were between 0 and 4.3 ml/min, the mean clearances of the total dialysis ranged between 1.1 and 3.4 ml/min. Total amount of teriflunomide removed was 5.8–8.8 μg per dialysis session. Dialytic removal of the active metabolite of leflunomide, teriflunomide (A77-1726), is negligible. Leflunomide can be used for RA patients on chronic dialysis without any dosage modification.

Keywords

Dialysis End-stage renal disease Leflunomide Pharmacokinetics Rheumatoid arthritis 

References

  1. 1.
    Product Information Immunosporin (Cyclosporine), Novartis Pharma, last update 9/2011Google Scholar
  2. 2.
    Product Information Azulfidine RA (Sulfasalazine), Pfizer, last update 5/2009Google Scholar
  3. 3.
    Product Information Lantarel (MTX), Pfizer, last update 11/2010Google Scholar
  4. 4.
    Product Information Arava (Leflunomide), Sanofi Aventis, last update 11/2011Google Scholar
  5. 5.
    Ellman MH, Ginsberg D (1990) Low-dose methotrexate and severe neutropenia in patients undergoing renal dialysis. Arthritis Rheum 33:1060–1061PubMedCrossRefGoogle Scholar
  6. 6.
    Boulanger H, Launay-Vacher V, Hierniaux P, Fau JB, Deray G (2001) Severe methotrexate intoxication in a haemodialysis patient treated for rheumatoid arthritis. Nephrol Dial Transplant 16:1087PubMedCrossRefGoogle Scholar
  7. 7.
    Yang CP, Kuo MC, Guh JY, Chen HC (2006) Pancytopenia after low dose methotrexate therapy in a hemodialysis patient: case report and review of literature. Ren Fail 28:95–97PubMedCrossRefGoogle Scholar
  8. 8.
    Teshima D, Hino B, Makino K, Yano T, Itoh Y, Joh Y, Iida M, Oishi R (2003) Sulphasalazine-induced leucopenia in a patient with renal dysfunction. J Clin Pharm Ther 28:239–242PubMedCrossRefGoogle Scholar
  9. 9.
    Smolen JS, Kalden JR, Scott DL, Rozman B, Kvien TK, Larsen A, Loew-Friedrich I, Oed C, Rosenburg R (1999) Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet 23(353):259–266CrossRefGoogle Scholar
  10. 10.
    Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G, Fox R, Moreland L, Olsen N, Furst D, Caldwell J, Kaine J, Sharp J, Hurley F, Loew-Friedrich I (1999) Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 159:2542–2550PubMedCrossRefGoogle Scholar
  11. 11.
    Rozman B (2002) Clinical pharmacokinetics of leflunomide. Clin Pharmacokinet 41:421–430PubMedCrossRefGoogle Scholar
  12. 12.
    Li J, Yao HW, Jin Y et al (2002) Pharmacokinetics of leflunomide in Chinese healthy volunteers. Acta Pharmacol Sin 23:551–555PubMedGoogle Scholar
  13. 13.
    Lucien J, Dias VC, Le Gatt DF, Yatscoff RW (1995) Blood distribution and single-dose pharmacokinetics of leflunomide. Ther Drug Monit 17:454–459PubMedCrossRefGoogle Scholar
  14. 14.
    Keller F, Wilms H, Schultze G, Offerman G, Molzahn M (1983) Effect of plasma protein binding, volume of distribution and molecular weight on the fraction of drugs eliminated by hemodialysis. Clin Nephrol 19:201–205PubMedGoogle Scholar
  15. 15.
    Bergner R, Dill K, Boerner D, Uppenkamp M (2002) Elimination of intravenously administered ibandronate in patients on hemodialysis: a monocenter open study. Nephrol Dial Transplant 17:1281–1285PubMedCrossRefGoogle Scholar
  16. 16.
    Dias VC, Lucien J, Le Gatt DF, Yatscoff RW (1995) Measurement of the active leflunomide metabolite (A77 1726) by reverse-phase high-performance liquid chromatography. Ther Drug Monit 17:84–88PubMedCrossRefGoogle Scholar
  17. 17.
    Beaman JM, Hackett LP, Luxton G, Illett KF (2002) Effect of hemodialysis on leflunomide plasma concentrations. Ann Pharmacother 36:75–77PubMedCrossRefGoogle Scholar
  18. 18.
    Iwamoto M, Homma S, Asano Y, Minota S (2005) Administration of leflunomide to a patient with rheumatoid arthritis on haemodialysis. Scand J Rheumatol 34:410–411PubMedCrossRefGoogle Scholar
  19. 19.
    Van Roon EN, Jansen TLTA, van de Laar MAFJ, Yska JP, Keuper R, Houtmann PM, Brouwers JRBJ (2005) Therapeutic drug monitoring of A77 1726, the active metabolite of leflunomide: serum concentrations predict response to treatment in patients with rheumatoid arthritis. Ann Rheum Dis 64:569–574PubMedCrossRefGoogle Scholar
  20. 20.
    Akiyama Y, Fujimaki T, Sakurai Y (2003) Pharmacokinetics of salazosulfapyridine in a hemodialysis patient. Ryumachi 43:569–576PubMedGoogle Scholar
  21. 21.
    Wall SM, Johansen MJ, Molony DA, Du Bose TD, Jaffe N, Madden T (1996) Effective clearance of methotrexate using high-flux hemodialysis membranes. Am J Kidney Dis 28:846–854PubMedCrossRefGoogle Scholar
  22. 22.
    Diskin CJ, Stokes TJ, Dansby LM, Radcliff L, Carter TB (2006) Removal of methotrexate by peritoneal dialysis and hemodialysis in a single patient with end-stage renal disease. Am J Med Sci 332:156–158PubMedCrossRefGoogle Scholar
  23. 23.
    Murashima M, Adamski J, Milone MC, Shaw L, Tsai DE, Bloom RD (2009) Methotrexate clearance by high-flux hemodialysis and peritoneal dialysis: a case report. Am J Kidney Dis 53:871–874PubMedCrossRefGoogle Scholar
  24. 24.
    Venkataramanan R, Ptachcinski RJ, Burckart GJ, Yang SL, Starzl TE, Van Theil DH (1984) The clearance of cyclosporine by hemodialysis. J Clin Pharmacol 24:528–531PubMedGoogle Scholar
  25. 25.
    Kullinger B, Wolfram J, Hamilton G, Horzemsky M, Kovarik J, Woloszczuk W, Steiner G (1990) Pharmacokinetics and metabolism of cyclosporine A in 19 hemodialysis patients. Transplant Proc 22:1702–1705PubMedGoogle Scholar

Copyright information

© Clinical Rheumatology 2012

Authors and Affiliations

  • Raoul Bergner
    • 1
  • Lena Peters
    • 1
  • Verena Schmitt
    • 1
  • Christian Löffler
    • 1
  1. 1.Medizinische Klinik A, Klinikum LudwigshafenLudwigshafenGermany

Personalised recommendations