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 175 renal transplant recipients were prospectively followed. [Tac]blood and [Tac]cells were determined at month three, six and twelve 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 month three, six and twelve, 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 hematocrit 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 hematocrit 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.