Pharmacokinetic Interactions between Calcineurin Inhibitors and Azole Antifungals in Hematopoietic Stem Cell Transplant Recipients

Calcineurin inhibitors are used as immunosuppressive agents for graft-versus-host disease (GVHD) prophylaxis in hematopoietic stem cell transplantation.Since azole antifungals are frequently used for prophylaxis and treatment of infection under immunosuppressive therapy,it is highly possible that azole antifungals will affect blood concentrations of calcineurin inhibitors by inhibiting the drug metabolizing enzyme cytochrome P450 (CYP) 3A4.However,dosage adjustment with individual azole antifungals when administered by different routes has yet to be fully examined.In this study,we examined the effect of azole antifungals on blood concentrations of tacrolimus administered by intravenous constant infusion and cyclosporine administered orally in hematopoietic stem cell transplant patients.Oral voriconazole increased the blood concentration/dose (C/D) ratio of tacrolimus 2.7-fold,a significant increase.Oral itraconazole and intravenous voriconazole increased the C/D ratio 2.4-fold and 2-fold,respectively,but these changes were not statistically significant.The effects of oral and intravenous fluconazole were less potent than those of voriconazole and itraconazole,and tended to increase the C/D ratio of tacrolimus by 1.5-fold.The potencies of interactions between these azole anitifungals and oral cyclosporine blood concentrations were similar to those for intravenous tacrolimus.In consideration of these results,the dosages of calcineurin inhibitors should be reduced by 50-65% when concomitantly administered with voriconazole or itraconazole,and by around 35% in the case of fluconazole.However,dosage adjustment for these drugs should also be based on therapeutic drug monitoring because of the large inter-individual variability of pharmacokinetic interactions.