Effect of fluconazole on the pharmacokinetics of everolimus and tacrolimus in a heart transplant recipient: Case report.

Abstract

Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) and has been used in combination with calcineurin inhibitors (tacrolimus and cyclosporine) to prevent allograft rejection following organ transplantation. In heart transplant recipients, everolimus should be maintained at a target blood concentration of 3-8ng/mL, in combination with reduced-dose calcineurin inhibitors and therefore, requires strict monitoring. Fluconazole, an azole antifungal agent, affects blood concentration of tacrolimus by inhibiting the cytochromes P450 (CYP) 3A4 and 3A5. Therefore, to avoid overexposure during everolimus-azole cotreatment, the dose of everolimus should be reduced. However, the mechanism of interaction between everolimus and fluconazole remains unclear. We report the case of a heart transplant recipient who experienced a 2.8-fold increase in everolimus clearance and a 3.5-fold increase in everolimus dosage, following withdrawal of fluconazole therapy. The clearance and dosage of tacrolimus increased 4.7- and 3.0-fold, respectively. The concentrations of everolimus and tacrolimus should be carefully monitored when administered concomitantly with fluconazole to heart transplant recipients. The patient in this case had a CYP3A5*1/*3 genotype, and CYP3A5 constituted the metabolic pathway. Therefore, concomitant use of fluconazole might have a relatively small impact on everolimus and tacrolimus pharmacokinetics in this case. .