CLINICALLY SIGNIFICANT DRUG-INTERACTIONS WITH CYCLOSPORINE - AN UPDATE

Since its approval in 1983 for immunosuppressive therapy in patients u ndergoing organ and bone marrow transplants, cyclosporin has had a maj or impact on organ transplantation. It has significantly improved 1-ye ar and 2-year graft survival rates, and decreased morbidity in kidney, liver, heart, heart-lung and pancreas transplantation. Several studie s have supported the efficacy of cyclosporin in preventing graft-versu s-host disease in bone marrow transplantation. Cyclosporin is also pos sibly effective in treating diseases of autoimmune origin and as an an tineoplastic agent. The introduction of therapeutic drug monitoring of cyclosporin was extremely useful because of the wide inter- and intra individual variability in the pharmacokinetics of cyclosporin after or al or intravenous administration. Optimal long term use of cyclosporin requires careful monitoring of the blood (or plasma) concentrations. Sustained and clinically significant drug-drug interactions can occur during long term therapy with cyclosporin. The coadministration of mul tiple drugs with cyclosporin could result in graft rejection, renal dy sfunction or other undesirable effects. Any interaction that leads to modified cyclosporin concentrations is of potential clinical importanc e. Cyclosporin itself may have significant effects on the pharmacokine tics and/or pharmacodynamics of coadministered drugs, such as digoxin, HMG-CoA reductase inhibitors and antineoplastic drugs affected by mul tidrug resistance. Many drugs have been shown to affect the pharmacoki netics and/or pharmacodynamics of cyclosporin. Interactions between cy closporin and danazol, diltiazem, erythromycin, fluconazole, itraconaz ole, ketoconazole, metoclopramide, nicardipine, verapamil, carbamazepi ne, phenobarbital (phenobarbitone), phenytoin, rifampicin (rifampin) a nd cotrimoxazole (trimethoprim/sulfamethoxazole) are well documented i n a large number of patients. Other interactions (such as those with a ciclovir, estradiol and imipenem) are documented only in isolated case studies.