INTERACTIONS OF CYCLOSPORINE IN RENAL-TRANSPLANT RECIPIENTS

Treatment with Cyclosporine has resulted in improved allograft survival. Cyclosporine metabolism occurs in the liver via hepatic cytochrome P-450IIIA microsomal enzyme. Pharmacokinetic drug interactions usually involve drugs which induce or inhibit the cytochrome P-450 system. We reviewed the Medical Charts of 53 renal transplant recipients immunosuppressed with Cyclosporine between 1985 and 1991. We analysed the relationship between Cyclosporine concentration, its dose and the change induced by concomitant administration of different drugs. Until December 1 988, Cyclosporine was measured by solid-phase radioimmunoassay (RIA) using a polyclonal antibody. This method measures Cyclosporine and some of its metabolites. Since January 1989, Cyclosporine was measured in whole blood by radioimmunoassay (RIA-Kit Sandimmun(R), Sandoz), which used a specific monoclonal antibody which binds Cyclosporine and a non-specific monoclonal antibody which binds Cyclosporine and its metabolites. The therapeutic range recommended by Sandoz in whole blood using the specific monoclonal antibody is 100 to 400 ng/ml. We present 3 cases of probable pharmacokinetic drug interactions with Cyclosporine. The first patient received concomitantly isoniazide (150 mg/day). Cyclosporine levels were between 600 and 2085 ng/ml despite the dose reduction from 10 to 1.5 mg/kg/day (Fig. 1) The dose reduction of isoniazide to 100 mg/day resulted in reduction of Cyclosporine levels. Until December 1988 with the polyclonal antibody the median was 320 ng/ml (range: 185 to 760 ng/ml; n = 11). Since January 1989, using the monoclonal antibody the median was 158 ng/ml (range: < 50 to 637 ng/ml; n = 36) with only 3 determinations over 400 ng/ml. The high Cyclosporine levels were probably due to direct inhibition of Cyclosporine metabolism by isoniazide. The second patient received concomitantly phenobarbital (100-200 mg/day) and valproic acid (800 mg/day) as anticonvulsant therapy. Cyclosporine levels were low in several determinations using the monoclonal antibody (median: 82 ng/ml; range: < 50-274 ng/ml; n = 37) with phenobarbital levels in the therapeutic range and valproic levels below the therapeutic range. Despite the dose reduction of phenobarbital to 50 mg/day and the high dose ot Cyclosporine (10 mg/kg/day) Cyclosporine levels continued low (in 3 determinations the highest level was 148 ng/ml). The probable mechanism f or the Cyclosporine and phenobarbital interaction was the enhanced metabolism of Cyclosporine through enzyme induction. In the third case, the administration of ketoconazole (600 mg/day per 3 days) resulted in toxic Cyclosporine levels (> 1000 ng/ml), measured with the polyclonal antibody, with deterioration of renal and liver function. The mechanism for this potentially dangerous interaction was probably the inhibition of the P-450 enzyme system. No changes were associated with ranitidine, cefazolin, nifedipine, propranolol, furosemide, atenolol, enalapril, phenytoin, cimetidine, norfloxacin, allopurinol, bromazepan, prazosin, amiloride, chlorthalidone, vancomycin, acyclovir, methyldopa, clonidine and deflazacort, at least in the doses used. No changes were associated with amiodarone or nifurtimox administration. These results show the importance ot periodical Cyclosporine dosages when different drugs are administered concomitantly.