D317 - Dose Adjustments of Tacrolimus Extended Release After Letermovir Initation in Kidney Transplant Recipients

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Author Block: K. D. Belfield¹, J. E. Marvin¹, G. Girone¹, R. Formica², M. Srinivas³, ¹Department of Transplant, Yale New Haven Hospital, New Haven, CT, ²Section of Nephrology, Yale School of Medicine, New Haven, CT, ³Department of Pharmacy, Yale New Haven Hospital, New Haven, CT
*Purpose: Tacrolimus (TAC) is primarily metabolized through CYP3A4, while letermovir (LTM) is both metabolized by CYP3A4 and is a moderate CYP3A4 inhibitor, increasing TAC exposure when co-administered. Data for IR TAC suggest 40-60% dose reductions, but the extent of this interaction is less characterized for TAC extended release (TacXR; Envarsus®). Differences in pharmacokinetics betweenTacIR and TacXR may cause variability in the magnitude of this interaction. This evaluation characterizes the impact of LTM on TacXR dosing in kidney transplant recipients (KTR).
*Methods: This retrospective, single center study included adult KTR who received LTM prophylaxis while on TacXR between 09/2023-09/2025. Patients <1 month post-transplant prior to LTM initiation, on CYP3A4 interacting therapies and without TacXR level at goal prior to LTM were excluded. The primary endpoint was the percent change in TacXR dose before and after LTM initiation. Secondary endpoints were CMV breakthrough/late infection, myelosuppression resolution (WBC >3, ANC >1.5 ALC >0.75), rejection and adverse effects. CYP3A5 genotype data was collected when available to evaluate pharmacogenomic (pgx) variability.
*Results: In 16 patients, the average TacXR dose significantly decreased after initiation of LTM (5.1 mg vs 3.5 mg; p = 0.0013). This represented a median reduction of 26.8% (IQR 14.3-42.4). The median time to reach the first therapeutic trough after LTM initiation was 12 days (IQR 6.3-25.8). Pgx data was available for six patients; three were CYP3A5 intermediate metabolizers with a median TacXR dose reduction of 33% (IQR 14-40), similar to the overall cohort.
*Conclusions: Although there was substantial inter-patient variability (SD ±30%), these findings suggest that an empiric 25-30% TacXR dose reduction at LTM initiation may provide a safe and standardized approach for management of this interaction. Unlike the 40% reduction suggested for TacIR, TacXR required a lower reduction of only ~25-30%, supporting formulation-specific dose adjustments to ensure adequate Tac exposure.