Disposition kinetics of ketoprofen into synovial fluid following systemic administration: Population pharmacokinetic analysis

Background: The disposition kinetics of ketoprofen into synovial fluid was estimated to predict the time course of ketoprofen concentration in synovial fluid in patients with arthritis. Methods: After repeated oral doses of ketoprofen 100 mg twice daily, ketoprofen concentrations of plasma and synovial fluid were determined at steady-state by high performance liquid chromatography(HPLC) in 17 arthritic patients. Plasma pharmacokinetic parameters were estimated from one compartmental open model and the penetration pharmacokinetic parameters into synovial fluid were estimated from nonlinear fitting to the effect compartment model using NONMEM®. Results: At steady-state, the observed peak concentrations of plasma and synovial fluid were 4.6 ± 3.2 μg/mi and 2.4 ± 1.9 μg/ml at 2 hours and 5 hours after the last dose, respectively. Plots of plasma ketoprofen concentration against synovial concentration showed anticlockwise hysteresis, suggesting the time delay in the distribution of ketoprofen into synovial fluid from plasma. The estimated average rate constant for the ketoprofen loss from synovial fluid(k_co) was 0.16 h^-1. From the simulation of ketoprofen concentration curves, the predicted C_max of synovial fluid was corresponded to 76.6 % of the plasma concentration(1.44 μg/ml vs 1. 88 μg/ml) and time lag of T_max between both fluid spaces was estimated to 3.1 hours. Conclusions: These results suggest that the time course of ketoprofen concentration in synovial fluid is different from plasma concentration time profile after systemic administration of ketoprofen. The effect compartment model approach appears to be useful to predict the kinetics of ketoprofen in synovial fluid from the plasma data.