DICLOFENAC COMBINED WITH CYCLOSPORINE IN TREATMENT-REFRACTORY RHEUMATOID-ARTHRITIS - LONGITUDINAL SAFETY ASSESSMENT AND EVIDENCE OF A PHARMACOKINETIC DYNAMIC INTERACTION/

Objective. (1) To characterize potential changes in diclofenac pharmac okinetics and renal function in patients with rheumatoid arthritis (RA ) treated with diclofenac and cyclosporine; (2) to prospectively colle ct longitudinal safety data during use of this drug combination. Metho ds. Twenty patients with severe, treatment refractory RA were sequenti ally treated with stable doses of diclofenac (100-200 mg/day) for one month followed by diclofenac combined with cyclosporine (3 mg/kg/day) for one month. Pharmacokinetic profiles of diclofenac were obtained at the end of each treatment period. Combined therapy was continued for an additional 5 months, during which doses of both drugs could be indi vidually titrated and safety data collected. Results, During co-admini stration, diclofenac exposure doubled, as shown by an average 104% inc rease in the area-under-the-curve. Diclofenac half-life was not altere d. Serum creatinine was significantly elevated from a baseline Value o f 0.8 +/- 0.1 mg/dl on diclofenac alone to 1.0 +/- 0.3 mg/dl after one month cc-administration with cyclosporine. The magnitude of creatinin e elevation was not correlated with that of change in diclofenac expos ure, suggesting the pharmacokinetic interaction per se may not additio nally contribute to the effect on renal function resulting from this d rug combination. During longterm treatment with both medications, pros pectively collected safety data indicated that renal function could be stabilized when drug doses were individually titrated in response to serial clinical and laboratory evaluations. The overall pattern of adv erse events and laboratory abnormalities in the study population were similar to those reported in patients with RA treated with other nonst eroidal antiinflammatory agents and concomitant cyclosporine. Conclusi on, Diclofenac can be safely combined with cyclosporine in the managem ent of RA when appropriate clinical monitoring and dose titrations are performed. Due to the pharmacokinetic interaction that increases dicl ofenac systemic exposure, it would be prudent to start combination the rapy with diclofenac doses at the lower end of the therapeutic dose ra nge.