Effect of letermovir initiation on tacrolimus concentrations among lung transplant recipients receiving concomitant azole antifungal prophylaxis.

Abstract

The antiviral letermovir has been increasingly used as off-label cytomegalovirus prophylaxis in solid organ transplant recipients. Observational studies have reported notable increases in tacrolimus (FK) exposure following letermovir; however, whether a significant interaction occurs in the setting of existing moderate-to-strong CYP3A4 inhibition is unknown. Therefore, the purpose of this study was to evaluate FK trough changes before and after letermovir among lung transplant recipients receiving azole antifungal prophylaxis. This retrospective cohort study included lung transplant recipients newly initiated on letermovir between 2019-2022 following valganciclovir intolerance. Tacrolimus doses and concentrations were collected up to 30 days before and after the letermovir start date. No pre-emptive FK dose adjustments occurred prior to letermovir initiation. Patients admitted to the hospital or lacking an appropriately timed trough in the pre- or post-period were excluded. A total of 78 lung transplant recipients receiving FK (1.5mg median total daily dose) and itraconazole (56.4%), isavuconazole (25.6%) or posaconazole (17.9%) prophylaxis were included. Letermovir was started at a median of 8.4 months post-transplant. The pre-/post-letermovir median FK trough was 9.6/9.0ng/mL (p = .151), median dose-corrected trough was 4.2/4.7ng/mL/mg (+11.9%, p = .032), and median weight-based dose-corrected trough was 362/326 [ng/mL]/[mg/kg/day] (-9.9%, p = .036). There was no significant difference in the proportion of patients within their goal trough range before and after letermovir initiation (62%vs. 72%, p = .229). Empiric FK dose adjustments do not appear warranted before letermovir initiation in lung transplant recipients receiving antifungal prophylaxis with moderate-to-strong CYP3A4 inhibitors.