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

Background: 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. Methods: 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. Results: A total of 78 lung transplant recipients receiving FK (1.5 mg 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 9.6/9.0 ng/mL (p = .151), median dose-corrected trough was 4.2/4.7 ng/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). Conclusion: Empiric FK dose adjustments do not appear warranted before letermovir initiation in lung transplant recipients receiving antifungal prophylaxis with moderate-to-strong CYP3A4 inhibitors. image