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Combined Effect of Inter- and Intrapatient Variability in Tacrolimus Exposure on Graft Impairment Within a 3-Year Period Following Kidney Transplantation: A Single-Center Experience

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

Tacrolimus is a cornerstone of the most immunosuppressive protocols after kidney transplantation, but its use is complicated by notable interpatient and intrapatient variability (IPV). The goal of this study was to evaluate whether or not tacrolimus IPV, or average dose-adjusted trough concentration (C0/D), during 6–12 months post-transplantation might have contributed to graft function decline in a 3-year period following kidney transplantation. After primary evaluation of individual effects of tacrolimus IPV and C0/D, the study aimed to estimate the combined effect of tacrolimus IPV and C0/D on composite endpoint (consisting of graft failure, chronic allograft dysfunction, chronic rejection, and doubling of serum creatinine concentration) in the period between 13 and 36 months after kidney transplantation. In addition, the goal was to analyze the impact of genetics on interpatient variability in tacrolimus exposure in the early and late post-transplantation periods.

Methods

The study enrolled 104 Caucasian patients and included 2541 patient examinations up to 36 months after kidney transplantation. All patients were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T gene polymorphism. Patients were divided into groups based on the tacrolimus IPV tertiles and the median value of average C0/D during 6–12 months post-transplantation.

Results

The results showed a more pronounced decline in estimated glomerular filtration rate values within the high IPV tertile group (p = 0.018), as well as within the low C0/D group (p = 0.013) in a 3-year period after kidney transplantation. The carriers of CYP3A5*1/*3 genotype had lower C0/D compared to the CYP3A5*3/*3 carriers during the entire study period, while the results for ABCB1 were inconsistent when considering tacrolimus C0/D. Patients with high IPV/low C0/D had significantly reduced graft survival compared to the other tacrolimus IPV/C0/D combination groups (i.e., high IPV/high C0/D, low IPV/low C0/D, low IPV/high C0/D) with the hazard ratio of 3.14 in Cox analysis for reaching the composite endpoint.

Conclusion

The findings of this study suggest that combined assessment of tacrolimus IPV and tacrolimus C0/D may categorize patients towards risk of graft deterioration in the long-term post-transplantation period.

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Acknowledgements

This study was supported by Ministry of Education, Science and Technological Development of Serbia—project number III 41018.

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Authors and Affiliations

Authors

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by NS, KD, BM, GP and MC. The first draft of the manuscript was written by NS, RVR, KD and TC. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Nikola Z. Stefanović.

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Funding

No funding was received to conduct this study.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Ethics Committee of Faculty of Medicine, University of Nis (no. 12-2307-2/5 from 10.03.2016. and no. 12-6972-2/5 from 02.07.2018)) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Availability of data and material

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Stefanović, N.Z., Veličković-Radovanović, R.M., Danković, K.S. et al. Combined Effect of Inter- and Intrapatient Variability in Tacrolimus Exposure on Graft Impairment Within a 3-Year Period Following Kidney Transplantation: A Single-Center Experience. Eur J Drug Metab Pharmacokinet 45, 749–760 (2020). https://doi.org/10.1007/s13318-020-00644-2

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