CYCLOSPORINE AND NONSTEROIDAL ANTIINFLAMMATORY DRUGS - EXPLORING POTENTIAL-DRUG INTERACTIONS AND THEIR IMPLICATIONS FOR THE TREATMENT OF RHEUMATOID-ARTHRITIS

A series of clinical pharmacology studies was performed to screen for possible pharmacokinetic/dynamic contributions to drug interactions re ported in rheumatoid arthritis patients receiving cyclosporine and non steroidal antiinflammatory drugs (NSAIDs). No clinically relevant phar macokinetic changes in any of the drugs were noted when single-dose cy closporine was coadministered during a steady-state regimen of aspirin , indomethacin, or piroxicam in healthy volunteers. Only with diclofen ac was an interaction observed whereby the diclofenac area under the c oncentration-rime curve was doubled in the presence of cyclosporine. B ased on the outcomes of the screening studies, steady-state coadminist ration of both diclofenac and cyclosporine was assessed in rheumatoid arthritis patients, confirming the drug interaction of diclofenac with cyclosporine. Although the drug interaction was accompanied by a sign ificant rise in serum creatinine, there was no apparent concentration- effect relationship, inasmuch as the increase in diclofenac exposure w as not related to the magnitude of increase in serum creatinine. Based on the results of these five drug-drug interaction studies and the kn own biotransformation pathways of nonsteroidal antiinflammatory drugs, it is speculated that the pharmacokinetic interaction, which is uniqu e to diclofenac, is caused by inhibition by cyclosporine of diclofenac 's first-pass metabolism. Caution and appropriate clinical monitoring are recommended whenever cyclosporine and NSAIDs are coadministered; h owever, diclofenac in particular should be administered near the lower end of its therapeutic range when it is initially combined with cyclo sporine in the treatment of rheumatoid arthritis.