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Drug Res (Stuttg) 2013; 63(12): 633-638
DOI: 10.1055/s-0033-1349889
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Pharmacokinetics and Bioequivalence Evaluation of Leflunomide Tablets in Korean Healthy Volunteers

Y.-J. Lim
1   Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea
,
E.-J. Shim
1   Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea
2   Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea
,
H.-S. Kim
1   Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea
2   Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea
,
M. Oh
1   Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea
,
J.-H. Shon
1   Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea
2   Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea
,
J.-G. Shin
1   Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea
2   Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea
,
B.-S. Moon
3   CJ CHEILJEDANG Corp., Seoul, Republic of Korea
,
G.-S. Song
3   CJ CHEILJEDANG Corp., Seoul, Republic of Korea
,
E.-Y. Kim
2   Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Republic of Korea
› Author Affiliations
Further Information

Publication History

received 17 April 2013

accepted 28 June 2013

Publication Date:
24 July 2013 (online)

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Abstract

Leflunomide is a disease-modifying antirheumatic drug. The purpose of this study was to evaluate the bioequivalence of a test drug (CJ leflunomide) and a commercially available reference drug (Arava®) at 2 doses (10 and 20 mg) in healthy Korean volunteers. This was a single-dose (28 individuals enrolled at each dose group), randomized, open-label, 2-way crossover study. The 2 treatment periods were separated by a 56-day wash-out interval. Blood sampling was conducted until 672 h after drug administration. Plasma teriflunomide (active metabolite of leflunomide) concentrations were determined, and pharmacokinetic parameters were calculated. Bioequivalence was evaluated using an ANOVA model, based on the AUCt and the Cmax after administration of leflunomide tablets. Bioequivalence was defined as the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of AUCt and Cmax for the test and reference drugs being within the range of 0.80–1.25. The GMRs (90% CI) for AUCt and Cmax were 0.9506 (0.9091–0.9941) and 0.9861 (0.9360–1.0389), respectively, in the 10 mg study, and 0.9524 (0.9101–0.9968) and 0.9740 (0.9314–1.0186), respectively, in the 20 mg study. The 90% CIs of AUCt and Cmax at each dose were within the accepted range for bioequivalence. Based on the results, the test drug (CJ leflunomide) was bioequivalent to the commercially available reference drug (Arava®) at both doses.

Key words

leflunomide - teriflunomide - bioequivalence - pharmacokinetics - safety
 

  • References

  • 1 Strand V. Recent advances in the treatment of rheumatoid arthritis. Clin Cornerstone 1999; 2: 38-50
    CrossrefPubMedSearch in Google Scholar
  • 2 Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis & Rheumatism 2002; 46: 328-346
    CrossrefPubMedSearch in Google Scholar
  • 3 O’Dell JR. Therapeutic strategies for rheumatoid arthritis. N Engl J Med 2004; 350: 2591-2602
    CrossrefPubMedSearch in Google Scholar
  • 4 Arndt U, Rittmeister M, Moller B. Drug therapy of rheumatoid arthritis. Orthopade 2003; 32: 1095-1103
    PubMedSearch in Google Scholar
  • 5 van Roon EN, Jansen TL, van de Laar MA et al. 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 2005; 64: 569-574
    CrossrefPubMedSearch in Google Scholar
  • 6 Breedveld FC, Dayer JM. Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann Rheum Dis 2000; 59: 841-849
    CrossrefPubMedSearch in Google Scholar
  • 7 Greene S, Watanabe K, Braatz-Trulson J et al. Inhibition of dihydroorotate dehydrogenase by the immunosuppressive agent leflunomide. Biochem Pharmacol 1995; 50: 861-867
    CrossrefPubMedSearch in Google Scholar
  • 8 Davis JP, Cain GA, Pitts WJ et al. The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase. Biochemistry 1996; 35: 1270-1273
    CrossrefPubMedSearch in Google Scholar
  • 9 Manna SK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. J Immunol 1999; 162: 2095-2102
    PubMedSearch in Google Scholar
  • 10 Kalden JR, Scott DL, Smolen JS et al. Improved functional ability in patients with rheumatoid arthritis – longterm treatment with leflunomide versus sulfasalazine. European Leflunomide Study Group. J Rheumatol 2001; 28: 1983-1991
    PubMedSearch in Google Scholar
  • 11 Sharp JT, Strand V, Leung H et al. Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Leflunomide Rheumatoid Arthritis Investigators Group. Arthritis Rheum 2000; 43: 495-505
    CrossrefPubMedSearch in Google Scholar
  • 12 Kraan MC, Reece RJ, Barg EC et al. Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers. Arthritis Rheum 2000; 43: 1820-1830
    CrossrefPubMedSearch in Google Scholar
  • 13 Smolen JS, Kalden JR, Scott DL et al. 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 1999; 353: 259-266
    CrossrefPubMedSearch in Google Scholar
  • 14 Strand V, Cohen S, Schiff M et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 1999; 159: 2542-2550
    CrossrefPubMedSearch in Google Scholar
  • 15 Emery P, Breedveld FC, Lemmel EM et al. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2000; 39: 655-665
    CrossrefPubMedSearch in Google Scholar
  • 16 Cohen S, Cannon GW, Schiff M et al. Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group. Arthritis Rheum 2001; 44: 1984-1992
    CrossrefPubMedSearch in Google Scholar
  • 17 Weinblatt ME, Kremer JM, Coblyn JS et al. Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 1999; 42: 1322-1328
    CrossrefPubMedSearch in Google Scholar
  • 18 Mladenovic V, Domljan Z, Rozman B et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. Results of a randomized, placebo-controlled, phase II study. Arthritis Rheum 1995; 38: 1595-1603
    CrossrefPubMedSearch in Google Scholar
  • 19 FDA . ARAVA® Tablets (leflunomide) 10 mg, 20 mg, 100 mg Label. sanofi-aventis U.S.: LLC; 2010
    Search in Google Scholar
  • 20 Chan V, Charles BG, Tett SE. Rapid determination of the active leflunomide metabolite A77 1726 in human plasma by high-performance liquid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci 2004; 803: 331-335
    PubMedSearch in Google Scholar
  • 21 KFDA . Guideline of bioequivalance test. Korea Food & Drug Administration 2008;
    PubMedSearch in Google Scholar
  • 22 Sokka T, Makinen H. Drug management of early rheumatoid arthritis – 2008. Best Pract Res Clin Rheumatol 2009; 23: 93-102
    CrossrefPubMedSearch in Google Scholar
  • 23 Kale VP, Bichile LS. Leflunomide: a novel disease modifying anti-rheumatic drug. J Postgrad Med 2004; 50: 154-157
    PubMedSearch in Google Scholar
  • 24 Li J, Yao HW, Jin Y et al. Pharmacokinetics of leflunomide in Chinese healthy volunteers. Acta Pharmacol Sin 2002; 23: 551-555
    PubMedSearch in Google Scholar
  • 25 Park JY, Kim KA, Lee YH et al. Pharmacokinetic comparison and bioequivalence of two leflunomide formulations in humans: a single dose, randomized, open-label, two-way crossover study. Int J Clin Pharmacol Ther 2010; 48: 291-295
    PubMedSearch in Google Scholar
  • 26 Agarwal S, Das A, Ghosh D et al. Comparative bioequivalence study of leflunomide tablets in Indian healthy volunteers. Arzneimittelforschung 2012; 62: 145-148
    Thieme ConnectPubMedSearch in Google Scholar
  • 27 Rozman B. Clinical pharmacokinetics of leflunomide. Clin Pharmacokinet 2002; 41: 421-430
    CrossrefPubMedSearch in Google Scholar
  • 28 Chan V, Charles BG, Tett SE. Population pharmacokinetics and association between A77 1726 plasma concentrations and disease activity measures following administration of leflunomide to people with rheumatoid arthritis. Br J Clin Pharmacol 2005; 60: 257-264
    CrossrefPubMedSearch in Google Scholar
  • 29 Li EK, Tam LS, Tomlinson B. Leflunomide in the treatment of rheumatoid arthritis. Clin Ther 2004; 26: 447-459
    CrossrefPubMedSearch in Google Scholar
  • 30 Smolen JS, Emery P. Efficacy and safety of leflunomide in active rheumatoid arthritis. Rheumatology (Oxford) 2000; 39 (Suppl. 01) 48-56
    CrossrefPubMedSearch in Google Scholar
  • 31 Van Roon EN, Jansen TL, Mourad L et al. Leflunomide in active rheumatoid arthritis: a prospective study in daily practice. Br J Clin Pharmacol 2004; 58: 201-208
    CrossrefPubMedSearch in Google Scholar
  • 32 Limited PRN. Questran Lite. Auckland 2010
    PubMed
  • 33 Golicki D, Newada M, Lis J et al. Leflunomide in monotherapy of rheumatoid arthritis: meta-analysis of randomized trials. Pol Arch Med Wewn 2012; 122: 22-32
    PubMedSearch in Google Scholar