Markedly elevated blood concentrations of everolimus during concomitant posaconazole therapy in a liver transplant recipient: a case report

Everolimus (EVL) is widely used as an immunosuppressive agent in combination with calcineurin inhibitors, including tacrolimus (TAC), after liver transplantation. Posaconazole (PSCZ) is a triazole antifungal agent used for the treatment and prophylaxis of invasive fungal infections. Because PSCZ is a potent inhibitor of cytochrome P450 (CYP) 3A4, clinically significant drug-drug interactions with CYP3A substrates may occur. Although both EVL and TAC are primarily metabolized by CYP3A4, quantitative clinical data regarding the relationship between EVL and PSCZ remain limited.

We report the case of a living-donor liver transplant patient receiving EVL and TAC who was treated with PSCZ for suspected allergic bronchopulmonary mycosis. During PSCZ therapy, the concentration/dose (C/D) ratios of EVL and TAC increased by approximately 15-fold and 6-fold, respectively. The PSCZ trough concentration reached 8.8 µg/mL, and the serum potassium level decreased 2.5 mmol/L. Both the magnitude of increase in TAC exposure and increase in EVL exposure were more pronounced than those reported previously. Excessive PSCZ exposure may have augmented CYP3A inhibition, and the greater dependence of EVL metabolism on CYP3A compared to TAC likely contributed to the marked elevation in EVL exposure.

This case suggests that the drug-drug interaction between EVL and PSCZ may be more pronounced than that between TAC and PSCZ in certain cases with high PSCZ concentrations. When PSCZ is co-administered with EVL, close monitoring of the EVL concentration is recommended. Therapeutic drug monitoring of PSCZ may also be considered in selected cases to optimize safety and avoid excessive exposure, particularly when adverse events are suspected or clinically significant drug-drug interactions are anticipated.