Monitoring the tacrolimus concentration in peripheral blood mononuclear cells of kidney transplant recipients

Marith I. Francke; Dennis A. Hesselink; Yi Li; Birgit C.P. Koch; Lucia E.A. de Wit; Ron H.N. van Schaik; Lin Yang; Carla C. Baan; Teun van Gelder; Brenda C.M. de Winter

doi:10.1111/bcp.14585

Monitoring the tacrolimus concentration in peripheral blood mononuclear cells of kidney transplant recipients

Marith I. Francke^*, Dennis A. Hesselink, Yi Li, Birgit C.P. Koch, Lucia E.A. de Wit, Ron H.N. van Schaik, Lin Yang, Carla C. Baan, Teun van Gelder, Brenda C.M. de Winter

^*Corresponding author for this work

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Abstract

Aims: Tacrolimus is a critical dose drug and to avoid under- and overexposure, therapeutic drug monitoring is standard practice. However, rejection and drug-related toxicity occur despite whole-blood tacrolimus pre-dose concentrations ([Tac]_blood) being on target. Monitoring tacrolimus concentrations at the target site (within peripheral blood mononuclear cells; [Tac]_cells) may better correlate with drug-efficacy. The aim of this study was to (1) investigate the relationship between [Tac]_blood and [Tac]_cells, (2) identify factors affecting the tacrolimus distribution in cells and whole-blood, and (3) study the relationship between [Tac]_cells and clinical outcomes after kidney transplantation. Methods: A total of 175 renal transplant recipients were prospectively followed. [Tac]_blood and [Tac]_cells were determined at Months 3, 6 and 12 post-transplantation. Patients were genotyped for ABCB1 1199G>A and 3435C>T, CYP3A4 15389C>T, and CYP3A5 6986G>A. Data on rejection and tacrolimus-related nephrotoxicity and post-transplant diabetes mellitus were collected. Results: Correlations between [Tac]_blood and [Tac]_cells were moderate to poor (Spearman's r = 0.31; r = 0.41; r = 0.61 at Months 3, 6 and 12, respectively). The [Tac]_cells/[Tac]_blood ratio was stable over time in most patients (median intra-patient variability 39.0%; range 3.5%–173.2%). Age, albumin and haematocrit correlated with the [Tac]_cells/[Tac]_blood ratio. CYP3A5 and CYP3A4 genotype combined affected both dose-corrected [Tac]_blood and [Tac]_cells. ABCB1 was not significantly related to tacrolimus distribution. Neither [Tac]_blood nor [Tac]_cells correlated with clinical outcomes. Conclusions: The correlation between [Tac]_blood and [Tac]_cells is poor. Age, albumin and haematocrit correlate with the [Tac]_cells/[Tac]_blood ratio, whereas genetic variation in ABCB1, CYP3A4 and CYP3A5 do not. Neither [Tac]_blood nor [Tac]_cells correlated with clinical outcomes.

Original language	English
Pages (from-to)	1918-1929
Number of pages	12
Journal	British Journal of Clinical Pharmacology
Volume	87
Issue number	4
DOIs	https://doi.org/10.1111/bcp.14585
Publication status	Published - Apr 2021

Bibliographical note

ACKNOWLEDGEMENTS: The authors would like to acknowledge the help of Ms S. Bahmanywith the development and operation of the PBMC tacrolimus assayand Mrs N. Shuker and Mrs R. Bouamar with the performance of therandomized controlled trial. The authors are grateful to the researchnurses Mrs M.J. Boer Verschragen, Ms M. Cadogan and Mrs N.J. deLeeuw-van Weenen for their valuable contribution to this clinicalstudy. The authors also wish to acknowledge the important contribu-tions of Prof. Dr S.P. Berger, Ms S. El Bouazaoui, Ms I. Buijt, DrsI. Noorlander, Ir. M. van Vliet, and Prof. Dr J. J. Weening. The authorswant to thank Mr E. de Jonge for the genotyping analysis.

Publisher Copyright: © 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society

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Francke, M. I., Hesselink, D. A., Li, Y., Koch, B. C. P., de Wit, L. E. A., van Schaik, R. H. N., Yang, L., Baan, C. C., van Gelder, T., & de Winter, B. C. M. (2021). Monitoring the tacrolimus concentration in peripheral blood mononuclear cells of kidney transplant recipients. British Journal of Clinical Pharmacology, 87(4), 1918-1929. https://doi.org/10.1111/bcp.14585

@article{3898addcc66d49d5beac17406fc4eaa1,

title = "Monitoring the tacrolimus concentration in peripheral blood mononuclear cells of kidney transplant recipients",

abstract = "Aims: Tacrolimus is a critical dose drug and to avoid under- and overexposure, therapeutic drug monitoring is standard practice. However, rejection and drug-related toxicity occur despite whole-blood tacrolimus pre-dose concentrations ([Tac]blood) being on target. Monitoring tacrolimus concentrations at the target site (within peripheral blood mononuclear cells; [Tac]cells) may better correlate with drug-efficacy. The aim of this study was to (1) investigate the relationship between [Tac]blood and [Tac]cells, (2) identify factors affecting the tacrolimus distribution in cells and whole-blood, and (3) study the relationship between [Tac]cells and clinical outcomes after kidney transplantation. Methods: A total of 175 renal transplant recipients were prospectively followed. [Tac]blood and [Tac]cells were determined at Months 3, 6 and 12 post-transplantation. Patients were genotyped for ABCB1 1199G>A and 3435C>T, CYP3A4 15389C>T, and CYP3A5 6986G>A. Data on rejection and tacrolimus-related nephrotoxicity and post-transplant diabetes mellitus were collected. Results: Correlations between [Tac]blood and [Tac]cells were moderate to poor (Spearman's r = 0.31; r = 0.41; r = 0.61 at Months 3, 6 and 12, respectively). The [Tac]cells/[Tac]blood ratio was stable over time in most patients (median intra-patient variability 39.0%; range 3.5%–173.2%). Age, albumin and haematocrit correlated with the [Tac]cells/[Tac]blood ratio. CYP3A5 and CYP3A4 genotype combined affected both dose-corrected [Tac]blood and [Tac]cells. ABCB1 was not significantly related to tacrolimus distribution. Neither [Tac]blood nor [Tac]cells correlated with clinical outcomes. Conclusions: The correlation between [Tac]blood and [Tac]cells is poor. Age, albumin and haematocrit correlate with the [Tac]cells/[Tac]blood ratio, whereas genetic variation in ABCB1, CYP3A4 and CYP3A5 do not. Neither [Tac]blood nor [Tac]cells correlated with clinical outcomes.",

author = "Francke, {Marith I.} and Hesselink, {Dennis A.} and Yi Li and Koch, {Birgit C.P.} and {de Wit}, {Lucia E.A.} and {van Schaik}, {Ron H.N.} and Lin Yang and Baan, {Carla C.} and {van Gelder}, Teun and {de Winter}, {Brenda C.M.}",

note = "ACKNOWLEDGEMENTS: The authors would like to acknowledge the help of Ms S. Bahmanywith the development and operation of the PBMC tacrolimus assayand Mrs N. Shuker and Mrs R. Bouamar with the performance of therandomized controlled trial. The authors are grateful to the researchnurses Mrs M.J. Boer Verschragen, Ms M. Cadogan and Mrs N.J. deLeeuw-van Weenen for their valuable contribution to this clinicalstudy. The authors also wish to acknowledge the important contribu-tions of Prof. Dr S.P. Berger, Ms S. El Bouazaoui, Ms I. Buijt, DrsI. Noorlander, Ir. M. van Vliet, and Prof. Dr J. J. Weening. The authorswant to thank Mr E. de Jonge for the genotyping analysis. Publisher Copyright: {\textcopyright} 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society",

year = "2021",

month = apr,

doi = "10.1111/bcp.14585",

language = "English",

volume = "87",

pages = "1918--1929",

journal = "British Journal of Clinical Pharmacology",

issn = "0306-5251",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "4",

}

TY - JOUR

T1 - Monitoring the tacrolimus concentration in peripheral blood mononuclear cells of kidney transplant recipients

AU - Francke, Marith I.

AU - Hesselink, Dennis A.

AU - Li, Yi

AU - Koch, Birgit C.P.

AU - de Wit, Lucia E.A.

AU - van Schaik, Ron H.N.

AU - Yang, Lin

AU - Baan, Carla C.

AU - van Gelder, Teun

AU - de Winter, Brenda C.M.

N1 - ACKNOWLEDGEMENTS: The authors would like to acknowledge the help of Ms S. Bahmanywith the development and operation of the PBMC tacrolimus assayand Mrs N. Shuker and Mrs R. Bouamar with the performance of therandomized controlled trial. The authors are grateful to the researchnurses Mrs M.J. Boer Verschragen, Ms M. Cadogan and Mrs N.J. deLeeuw-van Weenen for their valuable contribution to this clinicalstudy. The authors also wish to acknowledge the important contribu-tions of Prof. Dr S.P. Berger, Ms S. El Bouazaoui, Ms I. Buijt, DrsI. Noorlander, Ir. M. van Vliet, and Prof. Dr J. J. Weening. The authorswant to thank Mr E. de Jonge for the genotyping analysis. Publisher Copyright: © 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society

PY - 2021/4

Y1 - 2021/4

N2 - Aims: Tacrolimus is a critical dose drug and to avoid under- and overexposure, therapeutic drug monitoring is standard practice. However, rejection and drug-related toxicity occur despite whole-blood tacrolimus pre-dose concentrations ([Tac]blood) being on target. Monitoring tacrolimus concentrations at the target site (within peripheral blood mononuclear cells; [Tac]cells) may better correlate with drug-efficacy. The aim of this study was to (1) investigate the relationship between [Tac]blood and [Tac]cells, (2) identify factors affecting the tacrolimus distribution in cells and whole-blood, and (3) study the relationship between [Tac]cells and clinical outcomes after kidney transplantation. Methods: A total of 175 renal transplant recipients were prospectively followed. [Tac]blood and [Tac]cells were determined at Months 3, 6 and 12 post-transplantation. Patients were genotyped for ABCB1 1199G>A and 3435C>T, CYP3A4 15389C>T, and CYP3A5 6986G>A. Data on rejection and tacrolimus-related nephrotoxicity and post-transplant diabetes mellitus were collected. Results: Correlations between [Tac]blood and [Tac]cells were moderate to poor (Spearman's r = 0.31; r = 0.41; r = 0.61 at Months 3, 6 and 12, respectively). The [Tac]cells/[Tac]blood ratio was stable over time in most patients (median intra-patient variability 39.0%; range 3.5%–173.2%). Age, albumin and haematocrit correlated with the [Tac]cells/[Tac]blood ratio. CYP3A5 and CYP3A4 genotype combined affected both dose-corrected [Tac]blood and [Tac]cells. ABCB1 was not significantly related to tacrolimus distribution. Neither [Tac]blood nor [Tac]cells correlated with clinical outcomes. Conclusions: The correlation between [Tac]blood and [Tac]cells is poor. Age, albumin and haematocrit correlate with the [Tac]cells/[Tac]blood ratio, whereas genetic variation in ABCB1, CYP3A4 and CYP3A5 do not. Neither [Tac]blood nor [Tac]cells correlated with clinical outcomes.

AB - Aims: Tacrolimus is a critical dose drug and to avoid under- and overexposure, therapeutic drug monitoring is standard practice. However, rejection and drug-related toxicity occur despite whole-blood tacrolimus pre-dose concentrations ([Tac]blood) being on target. Monitoring tacrolimus concentrations at the target site (within peripheral blood mononuclear cells; [Tac]cells) may better correlate with drug-efficacy. The aim of this study was to (1) investigate the relationship between [Tac]blood and [Tac]cells, (2) identify factors affecting the tacrolimus distribution in cells and whole-blood, and (3) study the relationship between [Tac]cells and clinical outcomes after kidney transplantation. Methods: A total of 175 renal transplant recipients were prospectively followed. [Tac]blood and [Tac]cells were determined at Months 3, 6 and 12 post-transplantation. Patients were genotyped for ABCB1 1199G>A and 3435C>T, CYP3A4 15389C>T, and CYP3A5 6986G>A. Data on rejection and tacrolimus-related nephrotoxicity and post-transplant diabetes mellitus were collected. Results: Correlations between [Tac]blood and [Tac]cells were moderate to poor (Spearman's r = 0.31; r = 0.41; r = 0.61 at Months 3, 6 and 12, respectively). The [Tac]cells/[Tac]blood ratio was stable over time in most patients (median intra-patient variability 39.0%; range 3.5%–173.2%). Age, albumin and haematocrit correlated with the [Tac]cells/[Tac]blood ratio. CYP3A5 and CYP3A4 genotype combined affected both dose-corrected [Tac]blood and [Tac]cells. ABCB1 was not significantly related to tacrolimus distribution. Neither [Tac]blood nor [Tac]cells correlated with clinical outcomes. Conclusions: The correlation between [Tac]blood and [Tac]cells is poor. Age, albumin and haematocrit correlate with the [Tac]cells/[Tac]blood ratio, whereas genetic variation in ABCB1, CYP3A4 and CYP3A5 do not. Neither [Tac]blood nor [Tac]cells correlated with clinical outcomes.

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U2 - 10.1111/bcp.14585

DO - 10.1111/bcp.14585

M3 - Article

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AN - SCOPUS:85096636663

SN - 0306-5251

VL - 87

SP - 1918

EP - 1929

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

IS - 4

ER -

Monitoring the tacrolimus concentration in peripheral blood mononuclear cells of kidney transplant recipients

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