Nonsteroidal antiinflammatory drugs (NSAID's) promptly moderate the signs and symptoms of inflammation in rheumatoid arthritis (RA) but individual patients vary markedly in their clinical response to a given dose or a given NSAID. In order to increase the precision with which individual patients are treated with NSAID's we propose to test the hypothesis that there is a body fluid drug concentration versus clinical efficacy relationship for several of these drugs. If we can establish levels that are demonstrably therapeutic, with acceptable incidences of toxicity, we will attempt to use pharmacokinetic parameters, established in a given individual to enable us to predict the dose of drug needed to achieve therapeutic drug levels in that individual, thus optimizing his therapy. Further, we will attempt to establish a method to compare the various NSAID's thus establishing the relative order in which these drugs may best be used. Standard methods will be used to assess clinical response. Both total and unbound ("free") drug concentrations will be measured. For NSAID's with a long half-life (salicylate, naproxen) and relatively stable plateau drug concentrations, correlation of total and free plateau serum drug concentrations and clearance with efficacy may be sufficient. For tolmetin, with a short serum half-life, a number of pharmacokinetic parameters using total and free serum and synovial fluid samples will be analyzed in correlations with efficacy. Similarly, spinal fluid and serum "free" salicylate levels and pH will be examined in patients with salicylate overdoses to determine whether they correlated better than serum total drug levels with the patient's clinical status and outcome. From the clinical response rates and incidence of the various side effects, utility indices for each of the investigated drugs will be constructed. This will allow comparison among these drugs in a rational way for the first time to decide which drug to use in what order in RA. Further, the studies of naproxen and tolmetin, if successful, will establish serum level-response curves and will also establish a relatively reliable method to predict serum levels of these drugs in individual patients with RA.
NIH ExPorter
NIH ExPorter