Drug interaction between voriconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplant recipients

Abstract

Although voriconazole has been shown to interact with calcineurin inhibitors, this interaction has not been thoroughly examined. The purpose of this study was to evaluate the drug interaction between voriconazole and calcineurin inhibitors among recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-one recipients of allogeneic HSCT were evaluated. Those recipients had been on CsA (n ¼ 10) or tacrolimus (n ¼ 11) when voriconazole (400 mg per day orally, or 8 mg/kg per day, i.v.) was initiated. Trough concentrations of calcineurin inhibitors were measured before and periodically after initiating voriconazole to determine the concentration/dose (C/D) ratio of calcineurin inhibitors. Median C/D ratio significantly increased by initiating voriconazole: from 86.0 (range, 43.5-178.8) to 120.2 (range, 86.1-379.4) in CsA (Po0.05), and from 595.9 (range, 51.3-1643.3) to 890.7 (range, 94.1-4658.3) (ng/ml)/(mg/kg) in tacrolimus (Po0.01). Median increases in the C/D ratio did not differ significantly between CsA and tacrolimus (82.1%, ranging from À9.4 to 266.9% vs 115.6%, ranging from 25.4 to 307.6%). These results indicate that voriconazole alters the blood concentration of calcineurin inhibitors with a wide range of interindividual variability after allogeneic HSCT. Dose adjustment of calcineurin inhibitors on initiating voriconazole should not be decided uniformly, but determined on an individual basis by close monitoring of their blood concentrations.

Tacrolimus use in adult allogeneic stem cell transplant recipients receiving voriconazole: preemptive dose modification and therapeutic drug monitoring

“…In that study, measurement of baseline tacrolimus concentrations, followed by serial drug blood concentrations after the addition of voriconazole resulted in median tacrolimus blood concentrations, that is, 115% (25-308%) above the target range. 21 This study shows the large interpatient variability of the interaction and demonstrates the need for continued monitoring. It is important to note that a preemptive dose-reduction strategy was not used in their study.…”

Pharmacokinetics of CsA during the switch from continuous intravenous infusion to oral administration after allogeneic hematopoietic stem cell transplantation

“…With regard to other azole antifungal agents, not only oral but also intravenous administration of ITCZ significantly affected the blood concentration of CsA. [20][21][22] Concerning the interaction between VRCZ and CsA, Mori et al 23 reported that the administration of VRCZ to patients receiving CsA resulted in a significant increase in the concentration/dose ratio of CsA, but the route of VRCZ administration did not affect the changes in the concentration/dose ratio. If we consider these findings together, it may be reasonable to suggest that the interaction between azole antifungal agents and CsA is stronger when the antifungals are given orally, but the difference becomes unclear with ITCZ and VRCZ, as the interactions of these agents are stronger than that of FLCZ and can be detected even when they are given intravenously.…”

Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic SCT recipients

“…There are some studies describing a clinically significant drug interaction with calcineurin inhibitors in renal transplants and HSCT recipients. [18][19][20] In order to reduce the impact of other drug interactions, our study compared the initial concentration of calcineurin inhibitor, because at that time the patients were uniformly administered omeprazole, itraconazole, ciprofloxacin and acyclovir. In our study, the conditioning regimen also did not affect the initial concentration of the calcineurin inhibitor.…”