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

The Pharmacogenomics Journal volume 24, Article number: 4 (2024) Cite this article

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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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References

  1. McCormack PL, Keating GM. Tacrolimus: in heart transplant recipients. Drugs. 2006;66:2269–79. discussion 2280-2282

    Article  CAS  PubMed  Google Scholar 

  2. Söderlund C, Rådegran G. Immunosuppressive therapies after heart transplantation-The balance between under- and over-immunosuppression. Transplant Rev (Orlando). 2015;29:181–9.

    Article  PubMed  Google Scholar 

  3. Adie SK, Bitar A, Konerman MC, Dorsch MP, Andrews CA, Pogue K, et al. Tacrolimus time in therapeutic range and long-term outcomes in heart transplant recipients. Pharmacotherapy. 2022;42:106–11.

    Article  CAS  PubMed  Google Scholar 

  4. Baker WL, Steiger S, Martin S, Patel N, Radojevic J, Darsaklis K, et al. Association between time-in-therapeutic tacrolimus range and early rejection after heart transplant. Pharmacotherapy. 2019;39:609–13.

    Article  CAS  PubMed  Google Scholar 

  5. Sirota M, Heyrend C, Ou Z, Masotti S, Griffiths E, Molina K. Impact of tacrolimus variability on pediatric heart transplant outcomes. Pediatr Transplant. 2021;25:e14043.

    Article  CAS  PubMed  Google Scholar 

  6. Uno T, Wada K, Matsuda S, Terada Y, Oita A, Kawase A, et al. Impact of the CYP3A5*1 allele on the pharmacokinetics of tacrolimus in japanese heart transplant patients. Eur J Drug Metab Pharmacokinet. 2018;43:665–73.

    Article  CAS  PubMed  Google Scholar 

  7. Deininger KM, Vu A, Page RL, Ambardekar AV, Lindenfeld J, Aquilante CL. CYP3A pharmacogenetics and tacrolimus disposition in adult heart transplant recipients. Clin Transplant. 2016;30:1074–81.

    Article  CAS  PubMed  Google Scholar 

  8. Gijsen VMGJ, van Schaik RH, Elens L, Soldin OP, Soldin SJ, Koren G, et al. CYP3A4*22 and CYP3A combined genotypes both correlate with tacrolimus disposition in pediatric heart transplant recipients. Pharmacogenomics. 2013;14:1027–36.

    Article  CAS  PubMed  Google Scholar 

  9. Yu M, Liu M, Zhang W, Ming Y. Pharmacokinetics, pharmacodynamics and pharmacogenetics of tacrolimus in kidney transplantation. Curr Drug Metab. 2018;19:513–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Haufroid V, Mourad M, Van Kerckhove V, Wawrzyniak J, De Meyer M, Eddour DC, et al. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics. 2004;14:147–54.

    Article  CAS  PubMed  Google Scholar 

  11. Birdwell KA, Decker B, Barbarino JM, Peterson JF, Stein CM, Sadee W, et al. Clinical pharmacogenetics implementation consortium (CPIC) guidelines for CYP3A5 genotype and tacrolimus dosing. Clin Pharmacol Ther. 2015;98:19–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li J, Liu S, Fu Q, Zhang Y, Wang X, Liu X, et al. Interactive effects of CYP3A4, CYP3A5, MDR1 and NR1I2 polymorphisms on tracrolimus trough concentrations in early postrenal transplant recipients. Pharmacogenomics. 2015;16:1355–65.

    Article  CAS  PubMed  Google Scholar 

  13. Zuo X, Ng CM, Barrett JS, Luo A, Zhang B, Deng C, et al. Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis. Pharmacogenet Genom. 2013;23:251–61.

    Article  CAS  Google Scholar 

  14. Shi W-L, Tang H-L, Zhai S-D. Effects of the CYP3A4*1B genetic polymorphism on the pharmacokinetics of tacrolimus in adult renal transplant recipients: a meta-analysis. PLoS ONE. 2015;10:e0127995.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Pallet N, Jannot A-S, El Bahri M, Etienne I, Buchler M, de Ligny BH, et al. Kidney transplant recipients carrying the CYP3A4*22 allelic variant have reduced tacrolimus clearance and often reach supratherapeutic tacrolimus concentrations. Am J Transplant. 2015;15:800–5.

    Article  CAS  PubMed  Google Scholar 

  16. Bruckmueller H, Werk AN, Renders L, Feldkamp T, Tepel M, Borst C, et al. Which genetic determinants should be considered for tacrolimus dose optimization in kidney transplantation? A combined analysis of genes affecting the CYP3A locus. Ther Drug Monit. 2015;37:288–95.

    Article  CAS  PubMed  Google Scholar 

  17. Aouam K, Kolsi A, Kerkeni E, Ben Fredj N, Chaabane A, Monastiri K, et al. Influence of combined CYP3A4 and CYP3A5 single-nucleotide polymorphisms on tacrolimus exposure in kidney transplant recipients: a study according to the post-transplant phase. Pharmacogenomics. 2015;16:2045–54.

    Article  CAS  PubMed  Google Scholar 

  18. Liu M, Shaver CM, Birdwell KA, Heeney SA, Shaffer CM, Van Driest SL. Composite CYP3A phenotypes influence tacrolimus dose-adjusted concentration in lung transplant recipients. Pharmacogenet Genomics. 2022;32:209–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Déri M, Szakál-Tóth Z, Fekete F, Mangó K, Incze E, Minus A, et al. CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients. Sci Rep. 2021;11:21389.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bowton E, Field JR, Wang S, Schildcrout JS, Van Driest SL, Delaney JT, et al. Biobanks and electronic medical records: enabling cost-effective research. Sci Transl Med. 2014;6:234cm3.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Roden DM, Pulley JM, Basford MA, Bernard GR, Clayton EW, Balser JR, et al. Development of a large-scale de-identified DNA biobank to enable personalized medicine. Clin Pharmacol Ther. 2008;84:362–9.

    Article  CAS  PubMed  Google Scholar 

  22. Doligalski CT, Liu EC, Sammons CM, Silverman A, Logan AT. Sublingual administration of tacrolimus: current trends and available evidence. Pharmacotherapy. 2014;34:1209–19.

    Article  CAS  PubMed  Google Scholar 

  23. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briët E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993;69:236–9.

    Article  CAS  PubMed  Google Scholar 

  24. Flockhart DA, Thacker D, McDonald C, Desta Z. The flockhart cytochrome P450 drug-drug interaction table. https://drug-interactions.medicine.iu.edu/MainTable.aspx (accessed May 2022).

  25. Center for Drug Evaluation and Research. Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers. FDA. 2022. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers (accessed Mar 2023).

  26. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120:c179–184.

    Article  PubMed  Google Scholar 

  27. Lunde I, Bremer S, Midtvedt K, Mohebi B, Dahl M, Bergan S, et al. The influence of CYP3A, PPARA, and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients. Eur J Clin Pharmacol. 2014;70:685–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Luo X, Zhu L, Cai N, Zheng L, Cheng Z. Prediction of tacrolimus metabolism and dosage requirements based on CYP3A4 phenotype and CYP3A5 * 3 genotype in Chinese renal transplant recipients. Acta Pharmacologica Sinica. 2016;37:555–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. van Gelder T. Drug interactions with tacrolimus. Drug Saf. 2002;25:707–12.

    Article  PubMed  Google Scholar 

  30. Undre N, Dickinson J. Relative bioavailability of single doses of prolonged-release tacrolimus administered as a suspension, orally or via a nasogastric tube, compared with intact capsules: a phase 1 study in healthy participants. BMJ Open. 2017;7:e012252.

    Article  PubMed  PubMed Central  Google Scholar 

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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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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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