Articular Diffusion of Meloxicam After a Single Oral Dose

Objective To investigate the distribution of meloxicam in the human knee joint and to compare it with the inhibition of cyclo-oxygenase (COX) activity in synovial cells. Design Prospective pharmacokinetic study and in vitro laboratory investigation. Patients and participants 42 male and female patients aged 26 to 85 years hospitalised for rheumatic disease and requiring a diagnostic and/or therapeutic knee puncture. Methods After a single oral dose of meloxicam 15mg, synovial fluid and blood samples were collected once per patient at various intervals after administration. Meloxicam concentrations were determined by a validated high performance liquid chromatography assay, protein binding by equilibrium dialysis, and pharmacokinetic parameters were calculated by noncompartmental analysis from the mean drug concentration-time profiles. The inhibitory effect of meloxicam on COX activity was investigated separately in unstimulated or interleukin-1 β-stimulated human synovial cells from osteoarthritic patients. Results Meloxicam was found in synovial fluid at the earliest sampling time (1 hour). Peak concentrations were reached approximately 6 hours postdose in both plasma (842 µg/L) and synovial fluid (320 µg/L). A plateau was observed after the distribution phase (6 hours), corresponding to a constant ratio of drug concentration between synovial fluid and plasma of about 0.47. This ratio was higher in patients with acute inflammation (0.58) than in those with no inflammation (0.38). Meloxicam was extensively bound to protein, mainly to serum albumin. The area under the drug concentration-time curve (AUC) in plasma was more than 2.5 times that in synovial fluid. The AUC for free meloxicam was similar in plasma and synovial fluid. The 50% inhibitory concentrations (IC 50 ) for basal and stimulated COX activity in human synovial cells were 33.7 nmol/L+ (11.8 µg/L) and 2.0 nmol/L (0.70 µg/L), respectively. The free concentration of meloxicam in synovial fluid was higher than the IC 50 for stimulated COX activity from 6 to 36 hours postdose. Conclusion On the basis of free synovial concentrations and the IC 50 for stimulated COX activity, meloxicam is expected to have a long duration of action. Inhibition of COX activity is expected to be more marked in inflamed synovium compared with non-inflamed synovium.