*Purpose: Letermovir does not appear to share cross-resistance with ganciclovir and is not associated with nephrotoxicity or myelosuppressive effects, making it an attractive option for management of cytomegalovirus in solid organ transplant (SOT) recipients. Letermovir is a moderate inhibitor of cytochrome P450 3A4 and may lead to increased serum concentrations of tacrolimus. We conducted this study to assess the magnitude of this drug-drug interaction in clinical practice among SOT recipients receiving either immediate-release (IR) or extended-release (XR) tacrolimus upon starting letermovir therapy.

*Methods: This was an IRB-approved, single-center retrospective study of adult SOT recipients receiving IR or XR tacrolimus who began letermovir therapy (480 mg or 720 mg once daily) between January 2018 and July 2020. Patients were excluded if they were on concomitant medications that are known to interact with tacrolimus. Tacrolimus dose and trough concentrations were collected for 30 days before and after the initiation of letermovir. The primary outcome was normalized IR and XR tacrolimus dose requirements with and without concomitant letermovir therapy. Linear interpolation was used to estimate tacrolimus trough concentrations if a dose adjustment was not made on the same date that the trough was obtained. Sign-test was used to compare differences in weight-based dose and dose-corrected trough concentrations within the same patient while on/off letermovir.

*Results: A total of 14 SOT recipients were identified. Median patient age was 57 (IQR 44 – 68) years and 57% of patients were kidney transplant recipients. Patients were predominantly white (43%) and male (79%). Patients began treatment with letermovir at a median time of 263 (135 – 443) days post-transplant. Most patients received letermovir 480 mg once daily (57%). Median weight-based tacrolimus dose when used without letermovir was 0.09 (0.04 – 0.14) versus 0.05 (0.03 – 0.11) mg/kg/day when used concomitantly with letermovir, P=0.016 (Figure 1A). Dose-corrected trough concentrations of tacrolimus without letermovir was 1.54 (1.15 – 2.77) versus 2.16 (1.31 – 3.16) ng/mL/mg when used concomitantly with letermovir, P=0.013 (Figure 1B).

*Conclusions: An approximate tacrolimus dose reduction of 30% may be warranted when initiating letermovir to achieve a comparable dose-corrected trough concentration. Regardless of empiric adjustment, we recommend repeating a tacrolimus trough concentration within 5-7 days after starting letermovir.

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