Management of Everolimus and Voriconazole Interaction in Lung Transplant Patients

To analyze the impact of voriconazole administration on everolimus dose, trough concentrations and concentration/dose (C0/D) ratio in order to determine the appropriate management of this interaction in lung transplant patients.

A retrospective study of 16 of consecutive lung transplant patients on a stable everolimus-based regimen to which oral voriconazole was added from January 2013 to February 2014. Everolimus blood levels were measured using the Thermo Scientific QMS Everolimus Immunoassay on an ARCHITECT-C8000 analyzer. The Wilcoxon signed-rank test was used to assess the exposure parameter variations before, during, and after azole withdrawal. A statistical analysis was performed using SPSS version 19.0. P-value < 0.05 was considered statistically significant.

Sixteen patients were included. Voriconazole treatment led to a significant 8.7-fold increase in the everolimus C0/D ratio. Although initially the daily dose was reduced to 48.5% ± 20.5%, and subsequently to 79.5% ± 7.1%, the desired therapeutic levels were achieved in all patients when it was decreased to 86.6% ± 3.9%. After its withdrawal, the C0/D ratio returned to values similar to the baseline situation. The comparison of exposure parameters studied at stable moments, before and after the completion of azole treatment with the cotreatment period, revealed significant changes (P < 0.05).

Oral voriconazole is a strong inhibitor of everolimus metabolism, requiring a dose reduction of around 87%. At the time of azole withdrawal, the dose should be increased to achieve C0/D ratio values similar to the initial situation. In our clinical practice, for a safe coadministration, a preemptive decrease to 75% of everolimus dose with the first azole prescription is recommended. Close monitoring of the everolimus concentrations and corresponding dosage adjustments are necessary until the target levels are achieved during both periods.