Evaluation of the Drug Interactions between Cyclosporin A and Azole Antifungals in Hematopoietic Stem Cell Transplant Recipients

Abstract

Cyclosporin A (CyA) and azole antifungals are clinically co-administered to patients after allogeneic hematopoietic stem cell transplantation (HSCT). Since CyA is a substrate of P450 (CYP3A4) and/or P-glycoprotein in the liver and the intestine, concomitant use of CyA and azole antifungals might increase the concentration of CyA in the blood. The purpose of this study was to evaluate the effects of antifungals on the blood concentration of CyA in allogeneic HSCT recipients. When CyA was orally administered, the magnitude of drug interactions between CyA and the antifungals on CyA concentration were: oral itraconazole (ITZ) solution > voriconazole (VCZ) tablet > ITZ capsule > fluconazole (FCZ) capsule. The concentration/dose ratio of CyA increased with each antifungal but the difference from control was only significant with oral ITZ solution (P<0.001). When CyA was intravenously (iv.) administered, the magnitude of drug interactions on CyA clearance was: iv. ITZ injection and VCZ tablet > oral ITZ solution > FCZ capsule > iv. fosfluconazole injection and ITZ capsule. Significant decreases in CyA clearance versus control were seen with iv. ITZ injection (P<0.001), VCZ tablet and oral ITZ solution (P<0.05). The present study confirmed that the magnitude of the drug interactions between CyA and azole antifungals varies by dosage form as well as by the potency of the azole inhibitor. These results provide a better understanding of the drug interactions between immunosuppressants and azole antifungals. In addition, this information may contribute to the effectiveness and safety of immunosuppressant therapy.