Monitoring the tacrolimus concentration in peripheral blood mononuclear cells of kidney transplant recipients
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.
|kidney transplantation, peripheral blood mononuclear cell, pharmacogenetics, tacrolimus, therapeutic drug monitoring|
|British Journal of Clinical Pharmacology|
|Organisation||Department of Internal Medicine|
Francke, M.I. (Marith I.), Hesselink, D.A, Li, Y. (Yi), Koch, B.C.P, de Wit, L.E.A, van Schaik, R.H.N, … de Winter, B.C.M. (2020). Monitoring the tacrolimus concentration in peripheral blood mononuclear cells of kidney transplant recipients. British Journal of Clinical Pharmacology. doi:10.1111/bcp.14585