Impact of Letermovir on Voriconazole Concentrations in Lung Transplant Patients.

BACKGROUND

The use of letermovir for cytomegalovirus prophylaxis in lung transplant recipients is increasing. Letermovir may reduce voriconazole exposure through induction of CYP-mediated metabolism. This study compared voriconazole concentrations in lung transplant recipients with and without concomitant letermovir exposure.

METHODS

This single-center retrospective study evaluated lung transplant recipients on prophylactic voriconazole, stratified by letermovir use. Exclusion criteria included non-steady state concentrations, concomitant interacting medications, and extracorporeal membrane oxygenation. The primary outcome was achievement of first voriconazole concentrations meeting lower and higher target thresholds (≥ 0.5 and ≥ 1 mcg/mL). Secondary outcomes included concentration-to-dose (mg/kg/day) ratio and median first concentration (mcg/mL).

RESULTS

Twenty-four patients receiving voriconazole alone contributed 46 concentrations, while 14 patients receiving concomitant letermovir contributed 30 concentrations. Fewer patients in the concomitant group achieved first voriconazole concentrations ≥ 0.5 mcg/mL (23.3% vs. 34.8%, p = 0.29) and ≥ 1 mcg/mL (3.3% vs. 21.7%, p = 0.042). The concentration-to-dose ratio (0.174 vs. 0.266 L/kg, p = 0.16) and median first concentration (0.52 vs. 0.72 mcg/mL, p = 0.19) were also lower with concomitant therapy. One definite breakthrough fungal infection occurred in the concomitant group (3.3%) compared with two probable infections in the voriconazole-only group (4.3%). Breakthrough CMV viremia occurred in 14.3% and 16.7% of patients, respectively.

CONCLUSION

This is the first study evaluating the impact of concomitant letermovir on voriconazole exposure during the early posttransplant period in lung transplant recipients. Concomitant letermovir was associated with reduced attainment of target voriconazole concentrations, supporting routine therapeutic drug monitoring and consideration of empiric voriconazole dose escalation when these agents are co-administered.