Clinical Pharmacokinetics

, Volume 43, Issue 7, pp 467–478 | Cite as

Pharmacokinetics of Lumiracoxib in Plasma and Synovial Fluid

  • Graham Scott
  • Christiane Rordorf
  • Christine Reynolds
  • Jyoti Kalbag
  • Michael Looby
  • Slavica Milosavljev
  • Margaret Weaver
  • John P. Huff
  • Dennis A. Ruff
Original Research Article

Abstract

Background

umiracoxib is a new cyclo-oxygenase-2 (COX-2) selective inhibitor in development for the treatment of rheumatoid arthritis, osteoarthritis and acute pain.

Objective

To investigate the pharmacokinetics of lumiracoxib in plasma and knee joint synovial fluid from patients with rheumatoid arthritis.

Design

Open-label multiple-dose study evaluating the steady-state pharmacokinetics of lumiracoxib in plasma and synovial fluid after 7 days of treatment with lumiracoxib 400mg once daily.

Patient population

Males and females aged 18–75 years with rheumatoid arthritis, having moderate to significant synovial fluid effusion of the knee.

Outcome measures

Following a 7-day washout period for previous nonsteroidal anti-inflammatory drugs, 22 patients (17 female, 5 male) received lumiracoxib 400mg once daily for seven consecutive days. On day 7, following an overnight fast, a final dose of lumiracoxib was administered and serial blood and synovial fluid samples were collected for up to 28 hours. Lumiracoxib and its metabolites (4′-hydroxy-lumiracoxib and 5-carboxy-4′-hydroxy-lumiracoxib) were measured by validated high performance liquid chromatography-mass spectrometry methods. The steady-state pharmacokinetics of lumiracoxib were evaluated in plasma and synovial fluid by both a population pharmacokinetic model and noncompartmental analysis.

Results

Lumiracoxib was rapidly absorbed (peak plasma concentration at 2 hours) and the terminal elimination half-life in plasma was short (6 hours). Lumiracoxib concentrations were initially higher in plasma than in synovial fluid; however, from 5 hours after administration until the end of the 28-hour assessment period, concentrations of lumiracoxib were higher in synovial fluid than in plasma. Peak drug concentration in synovial fluid occurred 3–4 hours later than the peak plasma concentration. The mean steady-state trough concentration of lumiracoxib in synovial fluid (454 μg/L) was approximately three times higher than the mean value in plasma (155 μg/L), and the area under the concentration-time curve from 12 to 24 hours after administration was 2.6-fold higher for synovial fluid than for plasma. Median lumiracoxib protein binding was similar in plasma and synovial fluid (range 97.9–98.3%). Concentrations of 4′-hydroxy-lumiracoxib, the active COX-2 selective metabolite, remained low in comparison with parent drug in both plasma and synovial fluid. The concentration of lumiracoxib in synovial fluid at 24 hours after administration would be expected to result in substantial inhibition of prostaglandin E2 formation.

Conclusion

The kinetics of distribution of lumiracoxib in synovial fluid are likely to extend the therapeutic action of the drug beyond that expected from plasma pharmacokinetics. These data support the use of lumiracoxib in a once-daily regimen for the treatment of rheumatoid arthritis.

Keywords

Synovial Fluid Etodolac Tenoxicam Tiaprofenic Acid Population Pharmacokinetic Model 

References

  1. 1.
    Marnett LJ, Rowlinson SW, Goodwin DC, et al. Arachidonic acid oxygenation by COX-1 and COX-2: mechanisms of catalysis and inhibition. J Biol Chem 1999; 274: 22903–6PubMedCrossRefGoogle Scholar
  2. 2.
    Allison MC, Howatson AG, Torrance CJ, et al. Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 1992; 327: 749–54PubMedCrossRefGoogle Scholar
  3. 3.
    Vane JR, Botting RM. Mechanism of action of antiinflammatory drugs. Int J Tissue React 1998; 20: 3–15PubMedGoogle Scholar
  4. 4.
    Fitz Gerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001; 345: 433–42CrossRefGoogle Scholar
  5. 5.
    Fitzgerald GA. COX-2 and beyond: approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov 2003; 2: 879–90PubMedCrossRefGoogle Scholar
  6. 6.
    Gu H, Rodriguez L, Mangold J. In vitro determination of cytochrome P450 involvement in COX189 hepatic metabolism and drug-drug interaction potential. East Hanover (NJ): Novartis Pharmaceuticals Corporation, 2000. (Data on file)Google Scholar
  7. 7.
    Mangold JB, Gu H, Rodriguez LC, et al. Pharmacokinetics and metabolism of lumiracoxib in healthy male subjects [abstract]. Drug Metab Rev 2002; 34 (1 Suppl.): 141Google Scholar
  8. 8.
    Marshall PJ, Berry JC. Inhibition of thromboxane B2 and prostaglandin E2 from human whole blood in vitro by CGS 35189 and its metabolites. East Hanover (NJ): Novartis Pharmaceuticals Corporation, 2002. (Data on file)Google Scholar
  9. 9.
    Rordorf C, Scott G, Milosavljev S, et al. Steady state pharmacokinetics, pharmacodynamics, safety and tolerability of COX189 in healthy subjects [abstract]. Ann Rheum Dis 2002; 61 (1 Suppl.): 420Google Scholar
  10. 10.
    Scott G, Rordorf C, Milosavljev S, et al. Pharmacokinetics and pharmacodynamics of COX189 in patients with knee or hip primary osteoarthritis [abstract]. Ann Rheum Dis 2002; 61 (1 Suppl.): 128Google Scholar
  11. 11.
    Scott G, Branson J, Milosavljev S, et al. Lumiracoxib demonstrates dose-proportional and time-independent pharmacokinetics in patients with osteoarthritis of the knee [abstract]. Ann Rheum Dis 2003; 62 (1 Suppl.): 267Google Scholar
  12. 12.
    Scott G, Rordorf C, Milosavljev S, et al. Multiple-dose lumiracoxib shows rapid absorption and COX-2 selectivity without accumulation in patients with rheumatoid arthritis [abstract]. In: Tulunay FC, Orme M, editors. European collaboration: towards drug development and rational drug therapy. Proceedings of the Sixth Congress of the European Association for Clinical Pharmacology and Therapeutics. Berlin: Springer-Verlag, 2003: 124Google Scholar
  13. 13.
    Day RO, McLachlan AJ, Graham GG, et al. Pharmacokinetics of nonsteroidal anti-inflammatory drugs in synovial fluid. Clin Pharmacokinet 1999; 36: 191–210PubMedCrossRefGoogle Scholar
  14. 14.
    Dawson J, Jagher B, Toscano KT, et al. Lumiracoxib shows rapid distribution to inflamed sites in a rat tissue chamber model compared with rofecoxib and celecoxib [abstract]. Ann Rheum Dis 2003; 62 Suppl. 1: 377Google Scholar
  15. 15.
    Weaver ML, Flood DJ, Kimble EF, et al. Lumiracoxib demonstrates preferential distribution to inflamed tissue in the rat following a single oral dose: an effect not seen with other cyclooxygenase-2 inhibitors [abstract]. Ann Rheum Dis 2003; 62 Suppl. 1: 378Google Scholar
  16. 16.
    Graham GG. Kinetics of non-steroidal anti-inflammatory drugs in synovial fluid. Agents Actions Suppl 1988; 24: 66–75PubMedGoogle Scholar
  17. 17.
    Furst DE. Synovial fluid kinetics of non-steroidal anti-inflammatory drugs. Agents Actions Suppl 1985; 17: 65–78PubMedGoogle Scholar
  18. 18.
    Mäkelä A-L, Lempiäinen M, Ylijoki H. Ibuprofen levels in serum and synovial fluid. Scand J Rheumatol Suppl. 1981; 39: 15–7PubMedCrossRefGoogle Scholar
  19. 19.
    Day RO, Williams KM, Graham GG, et al. Stereoselective disposition of ibuprofen enantiomers in synovial fluid. Clin Pharmacol Ther 1988; 43: 480–7PubMedCrossRefGoogle Scholar
  20. 20.
    Fowler PD, Shadforth MF, Crook PR, et al. Plasma and synovial fluid concentrations of diclofenac sodium and its major hydroxylated metabolites during long-term treatment or rheumatoid arthritis. Eur J Clin Pharmacol 1983; 25: 389–94PubMedCrossRefGoogle Scholar
  21. 21.
    Emori HW, Champion GD, Bluestone R, et al. Simultaneous pharmacokinetics of indomethacin in serum and synovial fluid. Ann Rheum Dis 1973; 32: 433–5PubMedCrossRefGoogle Scholar
  22. 22.
    World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2000; 284: 3043–5CrossRefGoogle Scholar
  23. 23.
    Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315–24PubMedCrossRefGoogle Scholar
  24. 24.
    Holford NH, Sheiner LB. Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 1981; 6: 429–53PubMedCrossRefGoogle Scholar
  25. 25.
    Netter P, Bannwarth B, Royer-Morrot M-J. Recent findings on the pharmacokinetics of non-steroidal anti-inflammatory drugs in synovial fluid. Clin Pharmacokinet 1989; 17: 145–62PubMedCrossRefGoogle Scholar
  26. 26.
    Bertin P, Lapicque F, Payan E, et al. Sodium naproxen: concentration and effect on inflammatory response mediators in human rheumatoid synovial fluid. Eur J Clin Pharmacol 1994; 46: 3–7PubMedCrossRefGoogle Scholar
  27. 27.
    Aarons L, Salisbury R, Alam-Siddiqi M, et al. Plasma and synovial fluid kinetics of flurbiprofen in rheumatoid arthritis. Br J Clin Pharmacol 1986; 21: 155–63PubMedCrossRefGoogle Scholar
  28. 28.
    Day RO, Francis H, Vial J, et al. Naproxen concentrations in plasma and synovial fluid and effects on prostanoid concentrations. J Rheumatol 1995; 22: 2295–303PubMedGoogle Scholar
  29. 29.
    Dromgoole SH, Furst DE, Desiraju RK, et al. Tolmetin kinetics and synovial fluid prostaglandin E levels in rheumatoid arthritis. Clin Pharmacol Ther 1982; 32: 371–7PubMedCrossRefGoogle Scholar
  30. 30.
    Schnitzer TJ, Geusens P, Hasler P, et al. Efficacy and safety of COX189 in osteoarthritis: a multi-national study [abstract]. Arthritis Rheum 2000; 43 (9 Suppl.): S336Google Scholar
  31. 31.
    Tannenbaum H, Berenbaum F, Reginster J-Y, et al. Lumiracoxib is effective in the treatment of osteoarthritis of the knee: a 13-week, randomized, double-blind study versus placebo and celecoxib. Ann Rheum Dis. Epub 2004 Feb 27Google Scholar
  32. 32.
    Kraml M, Hicks DR, McKean M, et al. The pharmacokinetics of etodolac in serum and synovial fluid of patients with arthritis. Clin Pharmacol Ther 1988; 43: 571–6PubMedCrossRefGoogle Scholar
  33. 33.
    Brocks DR, Jamali F, Russell AS. Stereoselective disposition of etodolac enantiomers in synovial fluid. J Clin Pharmacol 1991; 31: 741–6PubMedGoogle Scholar
  34. 34.
    Nichol FE, Samanta A, Rose CM. Synovial fluid and plasma kinetics of repeat dose sustained action tiaprofenic acid in patients with rheumatoid arthritis. Drugs 1988; 35 (1 Suppl.): 46–51PubMedCrossRefGoogle Scholar
  35. 35.
    Lapicque F, Vergne P, Jouzeau J-Y, et al. Articular diffusion of meloxicam after a single oral dose: relationship to cyclooxygenase inhibition in synovial cells. Clin Pharmacokinet 2000; 39: 369–82PubMedCrossRefGoogle Scholar
  36. 36.
    Nilsen OG. Clinical pharmacokinetics of tenoxicam. Clin Pharmacokinet 1994; 26: 16–43PubMedCrossRefGoogle Scholar
  37. 37.
    Day RO, Williams KM, Graham S, et al. The pharmacokinetics of total and unbound concentrations of tenoxicam in synovial fluid and plasma. Arthritis Rheum 1991; 34: 751–60PubMedCrossRefGoogle Scholar
  38. 38.
    Scott G, Rordorf C, Blood P, et al. Dose escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of COX189 in healthy subjects [abstract]. Ann Rheum Dis 2002; 61 (1 Suppl.): 242Google Scholar
  39. 39.
    Fricke J, Zelenakas K, Jayawardene S, et al. Efficacy of COX189 compared to rofecoxib in the treatment of postoperative dental pain: a double-blind, randomized, placebo-controlled trial [abstract no. 953-P223]. World Congress on Pain (WCP); 2002 Aug 17–22; San DiegoGoogle Scholar
  40. 40.
    Weaver M, Milosavljev S. In vitro plasma protein binding of COX189 and three of its metabolites. East Hanover (NJ): Norvartis Pharmaceuticals Corporation, 2002. (Data on file)Google Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Graham Scott
    • 1
  • Christiane Rordorf
    • 2
  • Christine Reynolds
    • 3
  • Jyoti Kalbag
    • 3
  • Michael Looby
    • 2
  • Slavica Milosavljev
    • 3
  • Margaret Weaver
    • 4
  • John P. Huff
    • 5
  • Dennis A. Ruff
    • 6
  1. 1.Novartis PharmaceuticalsHorsham, West SussexUK
  2. 2.Novartis Pharma AGBaselSwitzerland
  3. 3.Novartis Pharmaceuticals CorporationEast HanoverUSA
  4. 4.Novartis Institutes for BioMedical ResearchCambridgeUSA
  5. 5.Arthritis Center of South TexasSan AntonioUSA
  6. 6.Healthcare DiscoveriesSan AntonioUSA

Personalised recommendations