Drug interaction between voriconazole and tacrolimus and its association with the bioavailability of oral voriconazole in recipients of allogeneic hematopoietic stem cell transplantation

Abstract

In a previous study, we noted wide inter-individual variability in drug interactions between voriconazole and tacrolimus, but that analysis did not take into account the routes of administration. In the present study, we analyzed interactions between these two drugs when both agents were administered orally after allogeneic hematopoietic stem cell transplantation (HSCT); the effect of plasma voriconazole levels on the magnitude of the drug interaction was also examined. Twenty-five allogeneic HSCT recipients were evaluated. Trough concentrations of tacrolimus were measured prior to, and periodically for 7-10 days after, initiating voriconazole (400 mg/day) to determine the concentration/dose (C/D) ratio of tacrolimus. The median C/D ratio of tacrolimus increased significantly from 172.8 (range 28.6-1110.7) to 537.5 (range 127.8-1933.3) (ng/mL)/(mg/kg) (P < 0.01) following initiation of voriconazole; the median increase was 138.8 % (range -32.0 to 685.7 %). The plasma concentration of voriconazole did not correlate with the increase of the tacrolimus C/D ratio (ρ = 0.16, P = 0.44). These results indicate that oral voriconazole has a significant drug interaction with oral tacrolimus with a wide inter-individual variability, which cannot be explained by the bioavailability of voriconazole. Other possible mechanisms should be explored in future studies.

Determinants of the Magnitude of Interaction Between Tacrolimus and Voriconazole/Posaconazole in Solid Organ Recipients

“…The proportional increase in Tac C/D (DC/D) resulting from azole co-therapy varied widely (almost 20-fold) between patients, in line with what has been previously observed in allogeneic hematopoietic stem cell transplantation (33). The proportional increase in Tac C/D (DC/D) resulting from azole co-therapy varied widely (almost 20-fold) between patients, in line with what has been previously observed in allogeneic hematopoietic stem cell transplantation (33).…”

Influence of azole antifungal drugs on blood tacrolimus levels after switching from intravenous tacrolimus to once‐daily modified release tacrolimus in patients receiving allogeneic hematopoietic stem cell transplantation

“…Metabolic interactions between tacrolimus and azole antifungal drugs are well known. It has been reported that FLCZ and VRCZ elevate blood tacrolimus levels . Our data regarding ( C iv / D iv )/( C po / D po ) ratios indicated that VRCZ increased blood tacrolimus concentrations more remarkably than FLCZ after conversion from intravenous to oral administration of tacrolimus.…”

“…Azole antifungal drugs are frequently used during the administration of tacrolimus to prevent fungal infections after HSCT. Azole antifungal drugs inhibit CYP3A activity and therefore increase the blood level of tacrolimus . In addition, the degree of CYP3A inhibition is known to vary among azole antifungal drugs .…”

Effect of Genetic Polymorphism of CYP3A5 and CYP2C19 and Concomitant Use of Voriconazole on Blood Tacrolimus Concentration in Patients Receiving Hematopoietic Stem Cell Transplantation

“…3 Although individual differences in drug response may vary because of age, sex, and disease, 4 the wide range of variability in TAC PK in HSCT recipients is often explained by polymorphisms in genes encoding metabolizing enzymes and drug interaction via metabolizing enzymes. [5][6][7] However, interindividual variability of blood TAC concentration during the early stages of HSCT is as of yet still difficult to predict.…”