Tacrolimus Dose Modification in Hematopoietic Cell Transplant Recipients Following a Change in Therapy from Fluconazole to Voriconazole

Antifungal therapy with voriconazole or fluconazole in combination with the calcineurin inhibitor tacrolimus exhibits significant CYP3A4 drug interaction potential in allogeneic hematopoietic cell transplant (HCT) recipients. The package insert for voriconazole has dosing recommendations for tacrolimus when voriconazole is started, but these do not apply to patients already receiving fluconazole therapy. The purpose of this retrospective study is to estimate appropriate dose modification of tacrolimus following a change in therapy from fluconazole to voriconazole. We performed a retrospective case-series analysis of five patients. The mean steady-state concentration/dose (C/D) ratio of tacrolimus increased from 413 (range, 255–642) to 850 (range, 670–953) following a switch from fluconazole to voriconazole ( ). This data represents a mean 2-fold increase in C/D ratios following the switch, indicating that the dose of tacrolimus may be most accurately reduced by approximately 50% following this switch in therapy. This provides some guidance for practitioners to estimate dose adjustments but will require close pharmacokinetic monitoring and adjustments on an individual patient basis. 1. Introduction Triazole antifungal agents are widely used for prophylaxis and treatment of invasive fungal infections in patients undergoing hematopoietic cell transplantation (HCT). Fluconazole is a commonly utilized agent because it exhibits excellent coverage of yeasts such as Candida species; however it is ineffective against molds and certain species of Candida. Due to its limited antifungal spectrum, fluconazole is utilized in patients who are at a low risk of acquiring invasive mold infections such as those due to Aspergillus species [1]. Alternatively, voriconazole is an extended-spectrum triazole antifungal agent that exhibits broad coverage of both yeasts and molds including Aspergillus. Therefore, patients undergoing HCT that are initiated on fluconazole are sometimes later switched to voriconazole in the event of a suspected or confirmed breakthrough fungal infection. Tacrolimus is a calcineurin inhibitor that is routinely used for prevention of graft versus host disease (GVHD) in patients undergoing allogeneic HCT. Both tacrolimus and triazole antifungal agents are metabolized by the cytochrome P450 enzyme system. Tacrolimus is primarily metabolized by the CYP3A4 isoenzyme subtype while the triazole antifungals fluconazole and voriconazole are metabolized by the CYP2C9, CYP2C19, and CYP3A4 isoenzymes in different degrees [2]. Due to this association, fluconazole