Pharmacodynamic/Pharmacokinetic Relationships for Rapidly Acting Drugs (NSAIDS) in Rheumatoid Arthritis: Problems and Preliminary Solutions
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.
KeywordsRheumatoid Arthritis Synovial Fluid Joint Tenderness Joint Tenderness Count Simple Linear Relationship
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- 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
- 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
- Furst, D. E (1988). Clinical evaluation of drugs in rheumatoid arthritis. Adv. Inflamm. Res., 12,227–238.Google Scholar
- 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
- 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
- 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
- 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
- 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
- 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