Abstract
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.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
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.
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.
Calin, A., J. Elswood, and P. T. Klorida (1989). Destructive arthritis, rheumatoid factor and HLA-DR4. Arth. Rheum.,32, 1221–1225.
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.
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.
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.
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.
Furst, D. E (1988). Clinical evaluation of drugs in rheumatoid arthritis. Adv. Inflamm. Res., 12,227–238.
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.
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.
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.
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, 666–669
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.
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.
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.
Lansbury, J., H. N. Baier, and S. McCracken (1962). Statistical study of variation in systemic and articular indexes. Arth. Rheum., 5, 445–456.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1993 Springer Science+Business Media New York
About this chapter
Cite this chapter
Furst, D.E. (1993). Pharmacodynamic/Pharmacokinetic Relationships for Rapidly Acting Drugs (NSAIDS) in Rheumatoid Arthritis: Problems and Preliminary Solutions. In: Yacobi, A., Skelly, J.P., Shah, V.P., Benet, L.Z. (eds) Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokinetics in Rational Drug Development. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-1520-0_20
Download citation
DOI: https://doi.org/10.1007/978-1-4757-1520-0_20
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4757-1522-4
Online ISBN: 978-1-4757-1520-0
eBook Packages: Springer Book Archive