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ORIGINAL RESEARCH article

Front. Microbiol.
Sec. Antimicrobials, Resistance and Chemotherapy
Volume 15 - 2024 | doi: 10.3389/fmicb.2024.1480874
This article is part of the Research Topic Benefit and Risk on Drug-drug Interactions in Infections View all articles

Drug-Drug Interactions between Letermovir and Tacrolimus in Japanese Renal Transplant Recipients Simulated Using a Physiologically Based Pharmacokinetic Model

Provisionally accepted
Takumi Maruyama Takumi Maruyama 1,2Hidefumi Kasai Hidefumi Kasai 3Yutaka Fukaya Yutaka Fukaya 4Mitsuru Shiokawa Mitsuru Shiokawa 1Toshimi Kimura Toshimi Kimura 4Yukihiro Hamada Yukihiro Hamada 2*
  • 1 Tokyo Women’s Medical University Hospital, Tokyo, Japan
  • 2 Kochi Medical School Hospital, Kochi, Kōchi, Japan
  • 3 Keio University, Kanagawa, Japan
  • 4 Juntendo University Hospital, Tokyo, Japan

The final, formatted version of the article will be published soon.

    Letermovir (LET) is a novel antiviral agent recently approved for cytomegalovirus (CMV) prophylaxis of renal transplant patients in Japan. However, its interactions with tacrolimus (TAC), an important immunosuppressant, remain ambiguous, warranting careful evaluation considering the unique genetic and physiological characteristics of Japanese patients. Therefore, in this study, we aimed to investigate the drug-drug interactions between LET and extended-release TAC (ER-TAC) in Japanese renal transplant patients via physiologically based pharmacokinetic (PBPK) modeling. We developed PBPK models for LET and TAC, including a new model for ER-TAC, using the Simcyp simulator. We also created a virtual Japanese post-transplant population by incorporating physiological parameters specific to Japanese patients, including CYP3A5 genotypes. Our model accurately predicted the pharmacokinetics of both immediate-release and ER-TAC co-administered with LET. In the Japanese population, LET significantly increased ER-TAC exposure, with the effect varying by CYP3A5 genotype. For CYP3A5*1 carrier, the area under the curve ratio ranged from 2.33 to 2.53, while for CYP3A5*3/*3 carriers, it ranged from 2.82 to 2.86. The maximum concentration ratio was approximately 1.50 across all groups. Our findings suggest reducing the ER-TAC dose by approximately 57-60% for CYP3A5*1 carrier and 65% for CYP3A5*3/*3 carriers when co-administered with LET for Japanese renal transplant patients. Moreover, the developed model incorporating population-specific factors, such as hematocrit values and CYP3A5 genotype frequencies, is a valuable tool to evaluate complex drug interactions and guide the dosing strategies for LET and TAC in Japanese patients. Overall, this study expands the application of PBPK modeling in transplant pharmacology, contributing to the development of effective immunosuppressive strategies for Japanese renal transplant patients.

    Keywords: physiologically based pharmacokinetic modeling, Drug-Drug Interaction, Letermovir, Tacrolimus, Renal transplantation, Japanese population

    Received: 14 Aug 2024; Accepted: 27 Sep 2024.

    Copyright: © 2024 Maruyama, Kasai, Fukaya, Shiokawa, Kimura and Hamada. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Yukihiro Hamada, Kochi Medical School Hospital, Kochi, Kōchi, Japan

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.