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Impact of CYP3A5 polymorphism on trough concentrations and outcomes of tacrolimus minimization during the early period after kidney transplantation

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The purpose of this study is to determine the impacts of CYP3A5 polymorphism on tacrolimus concentration and the proportion of patients within a target therapeutic range during the first week after transplantation together with the 3-month acute rejection rate in kidney transplant patients receiving a minimized tacrolimus regimen.

Methods

A total of 164 patients participated in the study. All received oral tacrolimus twice daily starting on the day of surgery with the target pre-dose (trough) concentration of 4–8 ng/ml for prevention of allograft rejection. Cytochrome P450 (CYP) 3A5 genotypes were determined. The patients were divided into CYP3A5 expressers (CYP3A5*1 allele carriers) and CYP3A5 nonexpressers (homozygous CYP3A5*3). Whole blood tacrolimus concentrations on days 3 and 7 posttransplantation and the incidence of biopsy-proven acute rejection (BPAR) at 3-month posttransplantation were compared between groups.

Results

On day 3, the median (IQR) dose-and-weight-normalized trough concentration in expressers and nonexpressers were 54.61 (31.98, 78.87) and 91.80 (57.60, 130.20) ng/ml per mg/kg/day, respectively (p < 0.001). Although only 47 and 42 % of expressers and nonexpressers were within the target range on day 3, approximately 60 % of both groups were within the target range on day 7. Proportions of BPAR among expressers and nonexpressers were 6.0 and 7.4 %, respectively (p = 0.723). The median (IQR) times to the first rejection in CYP3A5 expressers and nonexpressers were 32 (12, 68) and 15 (12, 37) days, respectively (p = 0.410).

Conclusions

Although CYP3A5 polymorphism significantly influenced the tacrolimus dose required to achieve the target concentration, the impact of CYP3A5 polymorphism on BPAR was not observed in this study.

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Acknowledgments

We would like to thank all the patients participating in this study and professor Dr. Sopon Jirasiritam, Dr. Sinee Disthabanchong, Dr. Montira Assanatham, and Dr. Arkom Nongnuch for their help with patient recruitment and providing clinical details. We would also like to thank the staff of Chulalongkorn University and Ramathibodi Hospital for their assistance. This research received a specific grant from the 90th Anniversary of Chulalongkorn University, Rachadapisek Sompote Fund. Astellas Pharma (Thailand) Co., Ltd. supported CYP3A5 genotyping at Ramathibodi Hospital. No pharmaceutical companies were involved in the study design, data collection, data analysis, or manuscript preparation.

Authors’ contributions

Khemjira Yaowakulpatana enrolled patients and collected and analyzed data. Somratai Vadcharavivad designed the study, analyzed data, interpreted data, and wrote the manuscript. Surasak Kantachuvesiri, Chagriya Kitiyakara, Atiporn Ingsathit, Supasil Sra-ium, and Nutthada Areepium designed the study and revised the manuscript. Bunyong Phakdeekitcharoen, Chonlaphat Sukasem, and Vasant Sumethkul revised the manuscript.

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Authors and Affiliations

  1. Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, 10330, Thailand

    Khemjira Yaowakulpatana, Somratai Vadcharavivad & Nutthada Areepium

  2. Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    Atiporn Ingsathit, Surasak Kantachuvesiri, Bunyong Phakdeekitcharoen, Vasant Sumethkul & Chagriya Kitiyakara

  3. Department of Pathology, Faculty of Medicine and Laboratory for Pharmacogenomics, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    Chonlaphat Sukasem

  4. Pharmacy Division, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

    Supasil Sra-ium

Authors
  1. Khemjira Yaowakulpatana
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  2. Somratai Vadcharavivad
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  10. Chagriya Kitiyakara
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Corresponding author

Correspondence to Somratai Vadcharavivad.

Ethics declarations

This study was approved by the ethics committee of Ramathibodi Hospital, Faculty of Medicine, Mahidol University, Thailand, and was conducted in accordance with the Declaration of Helsinki and its subsequent revisions. Written informed consent was obtained from all patients. This protocol was registered in ClinicalTrials.gov.ID NCT02377791.

Conflict of interest

Chagriya Kitiyakara received a research grant from Astellas Pharma (Thailand) Co., Ltd. The other authors declare no conflict of interest related to this work.

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Yaowakulpatana, K., Vadcharavivad, S., Ingsathit, A. et al. Impact of CYP3A5 polymorphism on trough concentrations and outcomes of tacrolimus minimization during the early period after kidney transplantation. Eur J Clin Pharmacol 72, 277–283 (2016). https://doi.org/10.1007/s00228-015-1990-0

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  • DOI: https://doi.org/10.1007/s00228-015-1990-0

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