Pharmacodynamic/Pharmacokinetic Relationships for Rapidly Acting Drugs (NSAIDS) in Rheumatoid Arthritis: Problems and Preliminary Solutions

  • Daniel E. Furst


The application of pharmacodynamic/pharmacokinetic (PK/PD) principles to anti-inflammatory therapy is hampered by a lack of knowledge about the etiologies of rheumatic diseases and a lack of precise endpoints of response.

For rheumatoid arthritis (RA), for example, the pathogenesis of disease is not well understood, making measurement of surrogate dynamic endpoints difficult. While measurement of T-cell numbers or response is possible, it does not accurately define the best therapeutic intervention.

Likewise, measurement of pharmacodynamic endpoints is inexact. For example, the coefficient of variation of joint tenderness count (a standard measure in RA) is about 25 percent, making measurement of drug effects difficult. And placebo response is also about 20–30 percent, further confounding efficacy.

Even the pharmacokinetics of NSAIDs may be complex and confound the ability to discern PK–PD relationships. Enantiomeric forms of some NSAIDs make previous measurements problematic. Thus, ibuprofen, given as a racemate, is about 60 percent converted in vivo to its active form, while other NSAIDs undergo much less interconversion.

Despite these obstacles, some relationships between response and drug concentrations have been discerned. For example, in two double-blind, cross-over studies, dose-response and serum concentration-response relationships were found for naproxen and carprofen, two NSAIDs. To do this, a nonparametric approach and simple linear relationships were used. Other studies relating to analgesis with NSAIDs have also been examined, as have relationships between salicylate levels and tinnitus.


Rheumatoid Arthritis Synovial Fluid Joint Tenderness Joint Tenderness Count Simple Linear Relationship 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Baber, N., L. Halliday, and W. J. A. Van den Heuvel (1979). Indomethacin in rheumatoid arthritis: Clinical effects, pharmacokinetics and platelet studies in responders and non-responders. Ann. Rheum. Dis.,38, 128–137.PubMedCrossRefGoogle Scholar
  2. Bacon, P. A. (1989). Extra articular rheumatoid arthritis. In D. J. McCarth (Ed.), Rheumatoid Arthritis and Allied Conditions 11th ed. Lea & Febiger, Philadelphia, pp. 1967–1988.Google Scholar
  3. Calin, A., J. Elswood, and P. T. Klorida (1989). Destructive arthritis, rheumatoid factor and HLA-DR4. Arth. Rheum.,32, 1221–1225.CrossRefGoogle Scholar
  4. Day, R. O., D. E. Furst, S. H. Dromgoole, B. Kamm, R. Roe, and H. E. Paulus (1982). Relationship of serum naproxen concentration to efficacy in rheumatoid arthritis. Clin. Pharmacol. Ther.,31, 733–740.PubMedCrossRefGoogle Scholar
  5. Day, R. O., G. G. Graham, D. Bieri, M. Brown, D. Cairns, G. Harris, J. Hounsell, S. Platt-Hepworth, R. Reeve, P. N. Sambrook, and J. Smith (1989). Concentration-response relationships for salicylate induced ototoxicity in normal volunteers. Br. J. Clin. Pharmacol.,28, 695–702.PubMedCrossRefGoogle Scholar
  6. Dromgoole, S. H., D. E. Furst, R. K. Desiraju, R. K. Nayak, M. A. Kirschenbaum, and H. E. Paulus (1982). Tolmetin kinetics and synovial fluid prostaglandin E levels in rheumatoid arthritis. Clin. Pharmacol. Ther.,32, 371–377.PubMedCrossRefGoogle Scholar
  7. Ekstrand, R., G. Alvan, M. L’Orme, R. Lewander, L. Palmer, and B. Sorby (1980). Double-blind dose response study of indomethacin in rheumatoid arthritis. Eur. J. Clin. Pharmacol.,17, 437–442.PubMedCrossRefGoogle Scholar
  8. Furst, D. E (1988). Clinical evaluation of drugs in rheumatoid arthritis. Adv. Inflamm. Res., 12,227–238.Google Scholar
  9. Furst, D. E., J. R. Caldwell, M. P. Klugman, D. Enthoven, K. Rittweger, R. Scheer, E. Sarkissian, and S. Dromgoole (1988). Serum concentration and dose-response relationships for carprofen in rheumatoid arthritis. Clin. Pharmacol. Ther.,44, 186–194.PubMedCrossRefGoogle Scholar
  10. Grennan, D. M., L. Aarons, M. Siddigui, M. Richards, R. Thompson, and C. Hingham (1983). Dose-response study with ibuprofen in rheumatoid arthritis: Clinical and pharmacokinetics. Br. J. Clin. Pharmacol.,15, 311–316.PubMedCrossRefGoogle Scholar
  11. Jalali, S., J. G. MacFarlane, E. M. Grace, and Y. B. Kassam (1986). Frequency of administration of short half-life nonsteroidal antiinflammatory analgesics (NSAIDs): Studies with ibuprofen. Clin. Exp. Rheum.,4, 91–93.Google Scholar
  12. Jamali, F., B. W. Berry, M. R. Tehrani, and A. S. Russell (1988). Stereoselective pharmacokinetics of flurbiprofen in humans and rats. J. Pharm. Sci. 77, 666–669PubMedCrossRefGoogle Scholar
  13. Knihinickik, R. D., K. M. Williams, and R. O. Day (1989). Chiral inversion of 2- arylproprionic acid non-steroidal anti-inflammatory drugs — 1. Biochem. Pharmacol.,38, 4389–4395.CrossRefGoogle Scholar
  14. Kowanko, I. C., M. S. Knapp, R. Pownall, and A. J. Swanell (1982). Domiciliary self-measurement in rheumatoid arthritis and the demonstration of circadian rhythmicity. Ann. Rheum. Dis.,41, 453–455.PubMedCrossRefGoogle Scholar
  15. Krane, S. M. (1989). Mechanisms of tissue destruction. In D. J. McCarth (Ed.), Rheumatoid Arthritis and Allied Conditions, 11th ed. Lea & Febiger, Philadelphia, pp. 698–714.Google Scholar
  16. Lansbury, J., H. N. Baier, and S. McCracken (1962). Statistical study of variation in systemic and articular indexes. Arth. Rheum., 5, 445–456.CrossRefGoogle Scholar
  17. Larsen, A., J. Horton, and C. Osborne (1983). Auranofin compared with intramuscular gold in the long-term treatment of rheumatoid arthritis: an x-ray analysis. In H. A. Capell, D. S. Cole, K. K. Manghani, and R. W. Morris (Eds.), Auranofin. Excerpta Medica. Amsterdam. pp. 264–277.Google Scholar
  18. McCarty, D. J. (1989). Clinical picture of rheumatoid arthritis. In D. J. McCarth (Ed.), Rheumatoid Arthritis and Allied Conditions 11th ed. Lea & Febiger, Philadelphia, pp. 715–743.Google Scholar
  19. Sharp, J. T., G. B. Bluhm, A. Brook, A. C. Brower, M. Corbett, J. L. Decker, H. K. Genant, J. P. Gofton, N. Goodman, A. Larsen, M. D. Lidsky, P. Pussila, A. S. Weinstein, B. N. Weissman, and D. Y. Young (1985). Reproducibility of multiple-observer scoring of radiologic abnormalities in the hands and wrists of patients with RA. Arth. Rheum., 28, 16–25.CrossRefGoogle Scholar
  20. Smythe, H. A., and W. W. Buchanan (1988). An experiment in reducing interobserver variability of the examination for joint tenderness. J. Rheum.,15, 492–494.PubMedGoogle Scholar
  21. Spiegel, T. M., W. King, S. R. Weiner, and H. E. Paulus (1987). Measuring disease activity: comparison of joint tenderness, swelling and ultrasonography in rheumatoid arthritis. Arth. Rheum.,30, 1283–1288.CrossRefGoogle Scholar
  22. Williams, H. J., J. R. Ward, S. L. Dahl, D. O. Clegg, R. F. Willkens, T. Oglesby, M. H. Weisman, S. Schlegel, R. M. Michaels, J. C. Luggen, M. J. Egger (1988). A controlled trial comparing sulfasalazine, gold sodium thiomalate and placebo in RA. Arth. Rheum.,31, 702–713.CrossRefGoogle Scholar
  23. Williams, H. J., R. F. Wilkens, C. O. Samuelson, G. S. Alarcon, M. Guttadauria, C. Yarboro, R. P. Polisson, S. R. Weiner, M. E. Luggen, L. M. Billingsley, D. L. Dahl, M. J. Egger, J. C. Redding, and J. R. Ward (1985). Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis: a controlled clinical trial. Arth. Rheum. 28, 721–730.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Daniel E. Furst
    • 1
    • 2
  1. 1.University of WashingtonSeattleUSA
  2. 2.Virginia Mason Medical Center (VMMC)SeattleUSA

Personalised recommendations