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Genotype-guided tacrolimus dosing in African-American kidney transplant recipients

The Pharmacogenomics Journal volume 17, pages 61–68 (2017)Cite this article

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Abstract

Tacrolimus is dependent on CYP3A5 enzyme for metabolism. Expression of the CYP3A5 enzyme is controlled by several alleles including CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5*7. African Americans (AAs) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AAs have primarily evaluated the CYP3A5*3 variant; however, there are other common nonfunctional variants in AAs (CYP3A5*6 and CYP3A5*7) that do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AAs are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AAs using a development and validation cohort. Time after transplant, steroid and antiviral use, age and CYP3A5*1, *3, *6 and *7 alleles were significant toward clearance. This study is the first to develop an AA-specific genotype-guided tacrolimus dosing model to personalize therapy.

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Acknowledgements

This project was supported by Grants (U19-AI070119 and U01-AI058013) from the National Institute of Allergy and Infectious Disease. We acknowledge the dedication of our coordinators and generous patients.

Author information

Author notes

  1. K Sanghavi, R C Brundage, M B Miller, D P Schladt, A K Israni, W Guan, W S Oetting, R B Mannon, R P Remmel, A J Matas and P A Jacobson: The DEKAF Investigators are listed before References.

Authors and Affiliations

  1. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

    K Sanghavi, R C Brundage, W S Oetting & P A Jacobson

  2. Department of Psychology, University of Minnesota, Minneapolis, MN, USA

    M B Miller

  3. Department of Nephrology and Chronic Disease Research Group, Minneapolis Medical Research Foundation, Hennepin County Medical Center, Minneapolis, MN, USA

    D P Schladt

  4. Department of Surgery, University of Minnesota, Minneapolis, MN, USA

    A K Israni & A J Matas

  5. Department of Biostatistics, University of Minnesota, Minneapolis, MN, USA

    W Guan

  6. Department of Nephrology, University of Alabama, Birmingham, AL, USA

    R B Mannon

  7. Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

    R P Remmel

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for the DEKAF Investigators

Corresponding author

Correspondence to P A Jacobson.

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Additional information

DeKAF Genomics Investigators

J Michael Cecka, UCLA Immunogenetics Center, Los Angeles, CA, USA. E-mail: mcecka@ucla.edu

Fernando G Cosio, Division of Nephrology, Mayo Clinic, Rochester, MN, USA. E-mail: Cosio.Fernando@mayo.edu

Robert Gaston, University of Alabama, Division of Nephrology, Birmingham, AL, USA. E-mail: rgaston@uab.edu

Sita Gourishankar, Division of Nephrology and Immunology, University of Alberta, Edmonton, Alberta, Canada. E-mail: sitag@ualberta.ca

Lawrence Hunsicker, Nephrology Division, Iowa City, IA, USA. E-mail: lawrence-hunsicker@uiowa.edu

Bertram Kasiske, Department of Medicine, Hennepin County Medical Center and the University of Minnesota, Minneapolis, MN, USA. E-mail: kasis001@umn.edu

David Rush, Health Sciences Center, Winnipeg, MB, Canada. E-mail: drush@exchange.hsc.mb.ca

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Sanghavi, K., Brundage, R., Miller, M. et al. Genotype-guided tacrolimus dosing in African-American kidney transplant recipients. Pharmacogenomics J 17, 61–68 (2017). https://doi.org/10.1038/tpj.2015.87

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