We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Association between CYP3A4, CYP3A5 and ABCB1 genotype and tacrolimus treatment outcomes among allogeneic HSCT patients

    Teresa T Ho‡

    *Author for correspondence:

    E-mail Address: teresa.ho@moffitt.org

    Department of Pharmacotherapeutics & Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL 33612, USA

    Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA

    ‡Authors contributed equally

    Search for more papers by this author

    ,
    Janelle B Perkins‡

    Department of Pharmacotherapeutics & Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL 33612, USA

    ‡Authors contributed equally

    Search for more papers by this author

    ,
    Rebecca Gonzalez

    Department of Blood & Marrow Transplant & Cellular Immunotherapy (BMT CI), H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA

    Department of Pharmacy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA

    ,
    James Kevin Hicks

    Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA

    ,
    Ronald Alvarez Martinez

    Department of Pharmacotherapeutics & Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL 33612, USA

    ,
    Katie Duranceau

    Department of Pharmacotherapeutics & Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL 33612, USA

    ,
    Brianna North

    Department of Pharmacotherapeutics & Clinical Research, University of South Florida Taneja College of Pharmacy, Tampa, FL 33612, USA

    ,
    Jongphil Kim

    Department of Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA

    ,
    Jamie K Teer

    Department of Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA

    ,
    Jiqiang Yao

    Department of Biostatistics & Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA

    ,
    Sean J Yoder

    Molecular Genomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA

    ,
    Taiga Nishihori

    Department of Blood & Marrow Transplant & Cellular Immunotherapy (BMT CI), H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA

    ,
    Nelli Bejanyan

    Department of Blood & Marrow Transplant & Cellular Immunotherapy (BMT CI), H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA

    ,
    Joseph Pidala

    Department of Blood & Marrow Transplant & Cellular Immunotherapy (BMT CI), H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA

    &
    Hany Elmariah

    Department of Blood & Marrow Transplant & Cellular Immunotherapy (BMT CI), H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA

    Published Online:https://doi.org/10.2217/pgs-2023-0204

    Aim: Successful treatment with tacrolimus to prevent graft versus host disease (GVHD) and minimize tacrolimus-related toxicities among allogeneic hematopoietic cell transplantation (alloHCT) recipients is contingent upon quickly achieving and maintaining concentrations within a narrow therapeutic range. The primary objective was to investigate associations between CYP3A4, CYP3A5 or ABCB1 genotype and the proportion of patients that attained an initial tacrolimus goal concentration following initiation of intravenous (iv.) and conversion to oral administration. Materials & methods: We retrospectively evaluated 86 patients who underwent HLA-matched (8/8) related donor alloHCT and were prescribed a tacrolimus-based regimen for GVHD prophylaxis. Results & conclusion: The findings of the present study suggests that CYP3A5 genotype may impact attainment of initial therapeutic tacrolimus concentrations with oral administration in alloHCT recipients.

    References

    • 1. Luznik L, O'Donnell PV, Symons HJ et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol. Blood Marrow Transplant 14(6), 641–650 (2008).
    • 2. Wingard JR, Nash RA, Przepiorka D et al. Relationship of tacrolimus (FK506) whole blood concentrations and efficacy and safety after HLA-identical sibling bone marrow transplantation. Biol. Blood Marrow Transplant 4(3), 157–163 (1998).
    • 3. Przepiorka D, Devine S, Fay J, Uberti J, Wingard J. Practical considerations in the use of tacrolimus for allogeneic marrow transplantation. Bone Marrow Transplant 24(10), 1053–1056 (1999).
    • 4. Hagen PA, Adams W, Smith S, Tsai S, Stiff P. Low mean post-transplantation tacrolimus levels in weeks 2–3 correlate with acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation from related and unrelated donors. Bone Marrow Transplant 54(1), 155–158 (2019).
    • 5. Ganetsky A, Shah A, Miano TA et al. Higher tacrolimus concentrations early after transplant reduce the risk of acute GvHD in reduced-intensity allogeneic stem cell transplantation. Bone Marrow Transplant 51(4), 568–572 (2016).
    • 6. Saeki T, Ueda K, Tanigawara Y, Hori R, Komano T. Human P-glycoprotein transports cyclosporin A and FK506. J. Biol. Chem. 268(9), 6077–6080 (1993).
    • 7. Dai Y, Hebert MF, Isoherranen N et al. Effect of CYP3A5 polymorphism on tacrolimus metabolic clearance in vitro. Drug Metab. Dispos. 34(5), 836–847 (2006).
    • 8. Birdwell KA, Decker B, Barbarino JM et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin. Pharmacol. Ther. 98(1), 19–24 (2015).
    • 9. Thervet E, Loriot MA, Barbier S et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin. Pharmacol. Ther. 87(6), 721–726 (2010).
    • 10. Clinical Pharmacogenetics Implementation Consortium. CYP3A5 frequency table. https://cpicpgx.org/guidelines/guideline-for-tacrolimus-and-cyp3a5/ (Accessed 15 May 2023).
    • 11. Elens L, Bouamar R, Hesselink DA et al. A new functional CYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokinetics in kidney transplant recipients. Clin. Chem. 57(11), 1574–1583 (2011).
    • 12. Elens L, Van Schaik RH, Panin N et al. Effect of a new functional CYP3A4 polymorphism on calcineurin inhibitors' dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenomics 12(10), 1383–1396 (2011).
    • 13. Elens L, Capron A, Van Schaik RH et al. Impact of CYP3A4*22 allele on tacrolimus pharmacokinetics in early period after renal transplantation: toward updated genotype-based dosage guidelines. Ther. Drug Monit. 35(5), 608–616 (2013).
    • 14. Zhou Y, Ingelman-Sundberg M, Lauschke VM. Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects. Clin. Pharmacol. Ther. 102(4), 688–700 (2017).
    • 15. Wang D, Guo Y, Wrighton SA, Cooke GE, Sadee W. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J. 11(4), 274–286 (2011).
    • 16. Wang D, Sadee W. CYP3A4 intronic SNP rs35599367 (CYP3A4*22) alters RNA splicing. Pharmacogenet. Genomics 26(1), 40–43 (2016).
    • 17. Scheibner A, Remmel R, Schladt D et al. Tacrolimus Elimination in Four Patients With a CYP3A5*3/*3 CYP3A4*22/*22 Genotype Combination. Pharmacotherapy 38(7), e46–e52 (2018).
    • 18. Walker AH, Jaffe JM, Gunasegaram S et al. Characterization of an allelic variant in the nifedipine-specific element of CYP3A4: ethnic distribution and implications for prostate cancer risk. Mutations in brief no. 191. Online. Hum. Mutat. 12(4), 289 (1998).
    • 19. Hamadeh IS, Zhang Q, Steuerwald N et al. Effect of CYP3A4, CYP3A5, and ABCB1 Polymorphisms on Intravenous Tacrolimus Exposure and Adverse Events in Adult Allogeneic Stem Cell Transplant Patients. Biol. Blood Marrow Transplant 25(4), 656–663 (2019).
    • 20. PharmGKB. Very Important Pharmacogene: ABCB1. www.pharmgkb.org/vip/PA166170352 (Accessed 15 May 2023).
    • 21. Khaled SK, Palmer JM, Herzog J et al. Influence of Absorption, Distribution, Metabolism, and Excretion Genomic Variants on Tacrolimus/Sirolimus Blood Levels and Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation. Biol. Blood Marrow Transplant 22(2), 268–276 (2016).
    • 22. Onizuka M, Kunii N, Toyosaki M et al. Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic SCT recipients. Bone Marrow Transplant 46(8), 1113–1117 (2011).
    • 23. Woodahl EL, Hingorani SR, Wang J et al. Pharmacogenomic associations in ABCB1 and CYP3A5 with acute kidney injury and chronic kidney disease after myeloablative hematopoietic cell transplantation. Pharmacogenomics J. 8(4), 248–255 (2008).
    • 24. Yanagimachi M, Naruto T, Tanoshima R et al. Influence of CYP3A5 and ABCB1 gene polymorphisms on calcineurin inhibitor-related neurotoxicity after hematopoietic stem cell transplantation. Clin. Transplant. 24(6), 855–861 (2010).
    • 25. Yanagisawa R, Katsuyama Y, Shigemura T et al. Engraftment syndrome, but not acute GVHD, younger age, CYP3A5 or MDR1 polymorphisms, increases tacrolimus clearance in pediatric hematopoietic SCT. Bone Marrow Transplant 46(1), 90–97 (2011).
    • 26. Pasternak AL, Zhang L, Hertz DL. CYP3A pharmacogenetic association with tacrolimus pharmacokinetics differs based on route of drug administration. Pharmacogenomics 19(6), 563–576 (2018).
    • 27. Przepiorka D, Weisdorf D, Martin P et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 15(6), 825–828 (1995).
    • 28. Jagasia MH, Greinix HT, Arora M et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol. Blood Marrow Transplant 21(3), 389–401.e381 (2015).
    • 29. Armand P, Gibson CJ, Cutler C et al. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood 120(4), 905–913 (2012).
    • 30. Holm S. A Simple Sequentially Rejective Multiple Test Procedure. Scandinavian Journal of Statistics. 6(2), 65–70 (1979). (Wiley).
    • 31. Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. The Annals of Statistics 16, 1141–1154 (1988).
    • 32. Gray RJ, Fine JP. A Proportional Hazards Model for the Subdistribution of a Competing Risk. Journal of the American Statistical Association 94(446), 496–509 (1999).
    • 33. Zhu J, Patel T, Miller JA et al. Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients. Int. J. Mol. Sci. 21(3), 858 (2020).
    • 34. Yamashita T, Fujishima N, Miura M et al. Effects of CYP3A5 polymorphism on the pharmacokinetics of a once-daily modified-release tacrolimus formulation and acute kidney injury in hematopoietic stem cell transplantation. Cancer Chemother. Pharmacol. 78(1), 111–118 (2016).
    • 35. Tacrolimus, package insert. Astellas Pharma Inc., IL, USA.
    • 36. Pasternak AL, Marcath LA, Li Y et al. Impact of Pharmacogenetics on Intravenous Tacrolimus Exposure and Conversions to Oral Therapy. Transplant Cell Ther. 28(1), 19.e11–19.e17 (2022).
    • 37. Kamdem LK, Streit F, Zanger UM et al. Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin. Chem. 51(8), 1374–1381 (2005).
    • 38. Suetsugu K, Mori Y, Yamamoto N et al. Impact of CYP3A5, POR, and CYP2C19 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplantation. Int. J. Mol. Sci. 20(10), 2413 (2019).
    • 39. Iwamoto T, Monma F, Fujieda A et al. Effect of Genetic Polymorphism of CYP3A5 and CYP2C19 and Concomitant Use of Voriconazole on Blood Tacrolimus Concentration in Patients Receiving Hematopoietic Stem Cell Transplantation. Ther. Drug Monit. 37(5), 581–588 (2015).
    • 40. Pallet N, Jannot AS, El Bahri M et al. Kidney transplant recipients carrying the CYP3A4*22 allelic variant have reduced tacrolimus clearance and often reach supratherapeutic tacrolimus concentrations. Am. J. Transplant 15(3), 800–805 (2015).
    • 41. Gijsen VM, Van Schaik RH, Elens L et al. CYP3A4*22 and CYP3A combined genotypes both correlate with tacrolimus disposition in pediatric heart transplant recipients. Pharmacogenomics 14(9), 1027–1036 (2013).
    • 42. Liu YY, Li C, Cui Z et al. The effect of ABCB1 C3435T polymorphism on pharmacokinetics of tacrolimus in liver transplantation: a meta-analysis. Gene 531(2), 476–488 (2013).
    • 43. Krupski MC, Bodiford A, Culos K. Tacrolimus Metabolism and Risk of Acute Graft Versus Host Disease. Blood 126(23), 1954 (2015).
    • 44. Moiseev IS, Burmina EA, Muslimov AR et al. Pharmacokinetic comparison of cyclosporin A and tacrolimus in graft-versus-host disease prophylaxis. Ann. Hematol. 96(6), 935–942 (2017).
    • 45. Sharma N, Zhao Q, Ni B et al. Effect of Early Post-Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation. Cancers (Basel) 13(4), 613 (2021).
    • 46. Saber W, Opie S, Rizzo JD, Zhang MJ, Horowitz MM, Schriber J. Outcomes after matched unrelated donor versus identical sibling hematopoietic cell transplantation in adults with acute myelogenous leukemia. Blood 119(17), 3908–3916 (2012).