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Composite CYP3A (CYP3A4 and CYP3A5) phenotypes and influence on tacrolimus dose adjusted concentrations in adult heart transplant recipients

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Abstract

CYP3A5 genetic variants are associated with tacrolimus metabolism. Controversy remains on whether CYP3A4 increased [*1B (rs2740574), *1 G (rs2242480)] and decreased function [*22 (rs35599367)] genetic variants provide additional information. This retrospective cohort study aims to address whether tacrolimus dose-adjusted trough concentrations differ between combined CYP3A (CYP3A5 and CYP3A4) phenotype groups. Heart transplanted patients (n = 177, between 2008 and 2020) were included and median age was 54 years old. Significant differences between CYP3A phenotype groups in tacrolimus dose-adjusted trough concentrations were found in the early postoperative period and continued to 6 months post-transplant. In CYP3A5 nonexpressers, carriers of CYP3A4*1B or *1 G variants (Group 3) compared to CYP3A4*1/*1 (Group 2) patients were found to have lower tacrolimus dose-adjusted trough concentrations at 2 months. In addition, significant differences were found among CYP3A phenotype groups in the dose at discharge and time to therapeutic range while time in therapeutic range was not significantly different. A combined CYP3A phenotype interpretation may provide more nuanced genotype-guided TAC dosing in heart transplant recipients.

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Fig. 1
Fig. 2: Tacrolimus C0/D from POD 2 to discharge by CYP3A phenotype.
Fig. 3: Analysis of tacrolimus C0/D from POD 2 to discharge by CYP3A4 phenotype.
Fig. 4: Analysis of tacrolimus C0/D from POD 2 to discharge by CYP3A5 phenotype.
Fig. 5: Tacrolimus dose at discharge by CYP3A phenotype.

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Funding

Support for this work is provided by funding from Vanderbilt University Medical Center’s BioVU (with data stored in Research Electronic Data Capture), which are supported by institutional funding and by the Clinical and Translational Science Award UL1 TR000445 from the National Institutes of Health’s National Center for Advancing Translational Sciences. ML is supported by Vanderbilt’s Maternal and Pediatric Precision in Therapeutics Center of Excellence of the National Institute of Child Health and Human Development project grant P50HD106446. SLV was supported by the National Institute of General Medical Sciences research project grant 1 R01 GM132204.

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Author notes

  1. These authors contributed equally: Michelle Liu, Savine Hernandez.

Authors and Affiliations

  1. Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN, USA

    Michelle Liu & Savine Hernandez

  2. Department of Pharmaceutical Sciences, University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA

    Christina L. Aquilante & Kimberly M. Deininger

  3. Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Joann Lindenfeld & Kelly H. Schlendorf

  4. Division of General Pediatrics, Department of Pediatrics, and Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Sara L. Van Driest

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  1. Michelle Liu
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Contributions

ML, SH, CLA, KMD, JL, KLS and SLV wrote the manuscript and interpreted results. ML and SLV designed the research study. ML and SD extracted data. ML analyzed data.

Corresponding author

Correspondence to Michelle Liu.

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Competing interests

ML, SH, CLA, JL, KHS and SLV declare no relevant conflicts of interest. KMD was an employee of University of Colorado at the time of this work and is currently an employee of Amgen Pharmaceuticals. SLV was an employee of Vanderbilt University Medical Center at the time of this work and is currently an employee of the National Institutes of Health, Office of the Director, All of Us Research Program.

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Liu, M., Hernandez, S., Aquilante, C.L. et al. Composite CYP3A (CYP3A4 and CYP3A5) phenotypes and influence on tacrolimus dose adjusted concentrations in adult heart transplant recipients. Pharmacogenomics J 24, 4 (2024). https://doi.org/10.1038/s41397-024-00325-2

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