Variable magnitude of drug interaction between oral voriconazole and cyclosporine A in recipients of allogeneic hematopoietic stem cell transplantation

Abstract

Drug interaction between voriconazole and calcineurin inhibitors is often problematic after allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. We previously demonstrated an unpredictable inter-individual variability in the magnitude of this drug interaction; however, the route of drug administration was not taken into account. In this study, the drug interaction between voriconazole and calcineurin inhibitors was further analyzed under the condition that both agents were administered orally. Twenty adult recipients of HSCT who had already been on a steady dose of oral cyclosporine A (CsA) and were started on oral voriconazole (400 mg/d) were eligible. The changes in the concentration/dose (C/D) ratio of CsA were evaluated by comparing the trough concentrations of CsA measured before and 7-10 d after initiating voriconazole. The median C/D ratio of CsA increased significantly from 64.1 to 114.3 (ng/mL)/(mg/kg) after initiating voriconazole (p < 0.01), and the median increase was 83.0% (range, 0.3-224.7%). The plasma concentration of voriconazole did not correlate significantly with the increase of the C/D ratio (ρ = -0.18, p = 0.45). These results indicate that the magnitude of drug interaction between oral voriconazole and CsA is widely variable, and it could not be explained by the difference in the blood levels of voriconazole. Further studies are required to elucidate the mechanism for this variability.

Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock

“…Cyclosporin A (CSA) a small molecule inhibitor of CypD binds CypD, antagonizes MPTP induction (Halestrap and Davidson, 1990; McGuinness et al, 1990; Nicolli et al, 1996), and prevents ischemia-re-oxygenation damage (Hausenloy et al, 2012). Federal Drug Administration approved CSA is being tested for treatment of heart attack and stroke, and is an immunosuppressant in graft vs. host disease (GVHD) for HCT (Junghanss et al, 2012; Kikuchi et al, 2012). To test MPTP involvement in EPHOSS mechanisms, and for possible protective effects of MPTP inhibition, BM was harvested in air with CSA.…”

Drug-interactions of azole antifungals with selected immunosuppressants in transplant patients: strategies for optimal management in clinical practice

“…Vice versa, discontinuation of voriconazole without dose adjustments of cyclosporine resulted in inadequate exposure of cyclosporine [45]. The great interindividual variability in cyclosporine AUC during concomitant voriconazole use indicates the magnitude of this interaction is widely variable [46,47]. At initiation of voriconazole, the cyclosporine dose should be reduced by 50%, with subsequent monitoring of cyclosporine blood concentrations.…”

“…At initiation of voriconazole, the cyclosporine dose should be reduced by 50%, with subsequent monitoring of cyclosporine blood concentrations. At discontinuation of voriconazole, the cyclosporine dose should be increased and cyclosporine blood concentrations should be carefully monitored [36,[44][45][46][47].…”

Primary antifungal prophylaxis during curative-intent therapy for acute myeloid leukemia

“…25 Indeed, unpredictable interactions between voriconazole and commonly used immunosuppressants (tacrolimus, cyclosporine A) are well documented. 67,68 Thus, voriconazole has no clear benefit over fluconazole or itraconazole in terms of efficacy, but is preferred over itraconazole due to better tolerability.Posaconazole. Two RCTs have evaluated posaconazole as prophylaxis in AML patients undergoing HCT.…”