B369 - Letermovir-Based Cytomegalovirus Prophylaxis with Tacrolimus and Everolimus Immunosuppression: Real-World Pharmacokinetic Interaction, Safety, and Viral Suppression

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Author Block: J. Uchida, N. Shunji, Y. Machida, T. Iwai, T. Naganuma, M. Kato, T. Yamasaki, T. Otoshi, K. Kuratsukuri, Urology, Osaka Metropolitan University, Osaka, Japan
*Purpose: Letermovir has demonstrated non-inferiority to valganciclovir for 200-day prophylaxis in cytomegalovirus (CMV) D⁺/R⁻ kidney transplant recipients, and its safety in both CMV D⁺/R⁻ and R⁺ recipients has been validated in global and Japanese phase III trials. It is approved in Japan for CMV prophylaxis in these populations. However, letermovir exhibits significant drug-drug interactions with calcineurin and mTOR inhibitors. This study evaluated the pharmacokinetic impact of letermovir initiation and discontinuation on tacrolimus and everolimus exposure, and assessed CMV prophylactic outcomes under a tacrolimus/everolimus regimen in kidney transplant recipients.
*Methods: This single-center, pilot observational study included 21 de novo kidney transplant recipients (D⁺/R⁻ or R⁺) who received reduced-dose tacrolimus plus everolimus with universal letermovir prophylaxis for approximately 200 days. Drug trough levels and renal function were monitored daily for 7 days at the initiation of letermovir (inpatient), and on days 0, 2-3, and 7 after its discontinuation (outpatient). CMV viral surveillance was performed monthly, and CMV infection was defined as a CMV PCR value exceeding 100 IU/mL. Percent changes in trough concentrations and dose adjustments of tacrolimus and everolimus before and after letermovir exposure, along with the incidence of CMV infection and adverse events, were analyzed until the completion of letermovir prophylaxis.
*Results: After the initiation of letermovir, tacrolimus trough levels increased by 30-40%, requiring approximately a 40% dose reduction. Everolimus trough levels also rose by around 40%, necessitating a similar dose reduction. Following letermovir discontinuation, tacrolimus trough levels decreased by approximately 40%, prompting a comparable dose increase, while everolimus levels declined by about 40%, requiring only a ~20% dose increase. Letermovir prophylaxis over 200 days was well tolerated, with clinically manageable adverse events, and no CMV infections were detected during the observation period. No unexpected graft dysfunction related to immunosuppressive overexposure was observed under strict therapeutic drug monitoring.
*Conclusions: Letermovir substantially increased tacrolimus and everolimus exposure, necessitating prompt dose reductions at initiation and reciprocal dose escalations after discontinuation, confirming a clinically significant yet predictable CYP3A-mediated interaction. With protocol-driven intensive therapeutic drug monitoring, these fluctuations were effectively managed without graft dysfunction or unexpected toxicity. This study demonstrated that letermovir prophylaxis, in combination with everolimus-based reduced tacrolimus therapy, was safe and effective throughout the prophylaxis period.