Drug Interaction Between Oral Voriconazole and Oral Calcineurin Inhibitor and Its Relationship with Blood Concentration of Voriconazole in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation

Drug interaction between calcineurin inhibitors (cyclosporine A (CsA) and tacrolimus) and voriconazole is well known. However, it has yet to be fully evaluated in the setting of hematopoietic stem cell transplantation (HSCT). We have previously shown a wide variability in the drug interaction between voriconazole and calcineurin inhibitors in HSCT recipients, which led to a conclusion that uniform reduction of the dose of calcineurin inhibitors was not recommended on initiating voriconazole. However, in that study, the route of administration of both drugs was not taken into consideration. In the present study, the magnitude of drug interaction between oral voriconazole and oral CsA was examined in HSCT recipients, and its relation with the blood concentration of voriconazole was also evaluated. Nineteen recipients of allogeneic HSCT who had already been on a steady dose of oral CsA, and were started on oral voriconazole (200 mg per body every 12 h) for the treatment or prophylaxis of fungal infection could be evaluated. The concentration/dose (C/D; (ng/ml)/(mg/kg)) ratio of CsA was calculated 7–10 days after initiating voriconazole when the increased blood levels of calcineurin inhibitors had stabilized. The plasma level of voriconazole was measure by high-performance liquid chromatography. The median C/D ratio of CsA significantly increased to 113.7 (ng/ml)/(mg/kg) (range, 62.4-189.5) after initiating voriconazole administration as compared with that before (63.1 (range, 41.1-189.0): P<0.001). Median increased rate of C/D ratios were 83.0% with a range of 0.3% to 224.7%. The plasma level of voriconazole on the day of evaluating C/D ratio was 1.98±0.84 mg/ml. The increased rate of C/D ratio of tacrolimus did not correlate with the plasma level of voriconazole (r = -0.17, P = 0.50). The magnitude of the drug interaction between oral CsA and oral voriconazole demonstrates a wide variability, whose increased rate of C/D ratio ranged between 0.3% and over 200%. This wide variability could not be explained by the bioavailability of voriconazole. The mechanisms of this variability should be explored in a future study.