Non-Steroidal Anti-Inflammatory Drugs: Pharmacokinetics and Clinical Response in Rheumatoid Arthritis

Comparative studies of non-steroidal anti-inflammatory drugs (NSAIDs) in rheumatoid arthritis indicate that patient response is variable and unpredictable. Although variability in pharmacokinetics might be implicated, no study has been able to demonstrate this. Changes in patient response to increments in dose or concentration have been difficult to detect, possibly due to the variable nature of the disease, to individual differences in disease severity and to the subjective nature of the rheumatological measurements. In this thesis the response to increments in dose or concentration of two NSAIDs, fenclofenac and naproxen, were investigated in patients with rheumatoid arthritis. In both cases three doses were given to all patients in a randomised double-blind design. Attention was focused on the determination of pharmacokinetic variability and the utility of plasma concentrations in the explanation of clinical response. In addition, the disposition of indomethacin in plasma and synovial fluid was studied. Analytical techniques were developed for the accurate measurement of plasma concentrations by high performance liquid chromatography and for the determination of the concentration of these drugs not bound to plasma proteins using equilibrium dialysis. The variability in the pharmacokinetics of the NSAIDs was assessed by performing single dose studies. There was considerable variability in the clearance of both fenclofenac and naproxen. The clearance of fenclofenac appeared to be reduced in patients with raised alkaline phosphatase and with increasing age. The clearance of naproxen was also reduced in the elderly and appeared to be lower in female patients