Evaluation of the Drug Interaction Between Intravenous High-Dose Fluconazole and Cyclosporine or Tacrolimus in Bone Marrow Transplant Patients

Abstract

The purpose of this open-label, prospective study was to compare steady state concentrations and clearances of intravenously administered cyclosporine or tacrolimus with and without concomitant high-dose (400 mg/day) fluconazole in allogeneic BMT patients. Twenty-one patients were evaluable. The mean steady state cyclosporine and tacrolimus concentrations without fluconazole were 320.3 and 18.2 ng/ml and increased to 389.2 and 21.2 ng/ml, respectively, after the addition of fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) increase. The mean steady state clearance of cyclosporine and tacrolimus without fluconazole was 6.82 and 1.28 ml/min/kg, which decreased to 5.57 and 1.10 ml/min/kg with fluconazole, corresponding to a 21% (P=0.031) and 16% (P=0.125) decrease, respectively. The 21% difference in the cyclosporine concentration and clearance was not thought to be clinically significant. These results suggest that fluconazole's interaction with cyclosporine or tacrolimus may be a result of fluconazole's inhibition of gut metabolism, resulting in a greater extent of absorption.

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

“…In a small prospective study in which fluconazole 400 mg daily was used in combination with tacrolimus in HSCT recipients, tacrolimus levels increased by 16% and tacrolimus clearance decreased by 16%. 17 A study in renal allograft recipients reported that tacrolimus patients with the CYP 3A5 3/*1 genotype (expressers) were less susceptible to fluconazole inhibition than CYP3A5*5 nonexpressers, suggesting that the magnitude of the azole-tacrolimus interaction could, in part, be explained by CYP3A expression. 18 In a prospective study in which tacrolimus was used in combination with itraconazole in HSCT recipients, tacrolimus levels were increased by a median 85%.…”

Change of the Blood Concentration of Tacrolimus after the Switch from Fluconazole to Voriconazole in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

“…In two reviews, 3,4) there was an impact of interaction between triazole antifungal agents and calcineurin inhibitors when both medicines were orally administered. In our result (Fig.…”

“…[2][3][4][7][8][9][10][11][12][13][14][15][16] Calcineurin inhibitors are routinely administered as prophylaxis for graft versus host disease (GVHD) in patients receiving allogeneic HSCT (allo-HSCT). [17][18][19] Triazole antifungal agents are metabolized by the cytochrome P450 (CYP) enzyme system, CYP2C9, CYP2C19, and CYP3A4 isozymes, 8,10) whereas the calcineurin inhibitors are primarily metabolized by CYP3A4.…”

“…Consequently, the concentrations of FK506 and CyA were increased when triazole antifungal agents were concomitantly administered. 3,4,[7][8][9][11][12][13][14][15][16] In vitro, the IC 50 value of VCZ against CYP3A4 activity was comparable with that of FCZ. 10) However, in vivo, Kami M., et al described…”

Tacrolimus: a new agent for the prevention of graft-versus-host disease in hematopoietic stem cell transplantation

“…Drug interactions with tacrolimus that are known to occur or for which a strong possibility for interaction exists are listed in Table 3. Agents known to induce or inhibit the P450 enzyme system should be administered with caution to patients receiving tacrol- Table 3 Potential drug interactions with tacrolimus 27,30,115,116,[120][121][122][123][124][125][126][127][128][129] imus, and close therapeutic drug monitoring should be performed. Pharmacokinetic studies in BMT patients who received tacrolimus alone or in combination with methylprednisolone or methotrexate showed no difference in clearance of tacrolimus.…”