Interaction between cyclosporine and fluconazole in renal allograft recipients

To determine the effect of fluconazole on cyclosporine concentrations, we used a randomized, double-blind, placebo-controlled study design to evaluate 16 stable renal transplant recipients receiving a constant cyclosporine dose. The two groups of patients were given identical capsules of either placebo or fluconazole 200 mg daily for 14 days. Compliance with the protocol was ensured by watching each patient take all the drug doses. Frequent whole-blood cyclosporine trough concentrations, measured by high-performance liquid chromatography, and two area under the blood concentration time curves were determined before and after 14 days of fluconazole or placebo. The results show that cyclosporine trough concentrations, in patients given fluconazole, increased from a mean +/- SD of 27 +/- 16 to 58 +/- 28 ng/ml (P = 0.001) while patients given placebo did not change--35 +/- 26 vs. 37 +/- 35 ng/ml (P = 0.7). Mean cyclosporine AUC increased in the fluconazole patients from 2167 +/- 1039 to 3989 +/- 1675 ng.hr/ml (P = 0.02) while the placebo patients did not change, 3089 +/- 2439 vs. 2954 +/- 2216 ng.hr/ml (P = 0.9). The pre- and post-treatment cyclosporine AUC difference (day 16 minus day 2) for fluconazole vs. placebo was 1822 +/- 1083 vs. -134 +/- 831 ng.hr/ml (P = 0.001). Mean cyclosporine clearance decreased an average of 55% in the fluconazole patients from 1.2 +/- 0.5 to 0.7 +/- 0.4 ml/hr.kg (P = 0.03); the placebo patients did not change--1.4 +/- 1.1 vs. 1.7 +/- 2.3 ml/hr.kg (P = 0.07). During the study period, serum creatinine concentrations did not increase after fluconazole vs. placebo treatment; they were 1.4 +/- 0.3 vs. 1.3 +/- 0.3 mg% (P = 0.8) initially, and 1.4 +/- 0.2 vs. 1.3 +/- 0.3 mg% (P = 0.5) after 14 days. This study indicates that fluconazole 200 mg daily can slowly increase cyclosporine concentrations over two weeks of therapy, approximately doubling the cyclosporine trough concentrations. The management of this interaction requires prospective planning for adjustments in the cyclosporine dosage, guided by cyclosporine concentrations, while transplant recipients are receiving fluconazole.