Dataset Information

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.

SUBMITTER: Francke MI

PROVIDER: S-EPMC8056738 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCalcineurin inhibitors, including tacrolimus, remain a cornerstone of immunosuppressive therapy after kidney transplantation. However, the therapeutic window is narrow, and nephrotoxic side effects occur with overdose, while the risk of alloimmunization and graft rejection increases with underdose. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) allows quantification of tacrolimus in biological samples from patients. This study investigates the feasibility of quantifying tacrolimus in scalp hair from kidney transplant (KT) recipients and correlates hair tacrolimus concentrations with tacrolimus dosage and blood trough levels. The aim was to provide proof-of-principle for hair tacrolimus drug monitoring in KT recipients.MethodSingle-center prospective study between September 9, 2021 and December 4, 2021, including KT recipients under tacrolimus. Minors, patients with active skin or hair diseases, and patients with scalp hair shorter than 4 cm were excluded from participation. Scalp hair was collected from the posterior vertex of patients, cut into segments, and analyzed for tacrolimus by LC-MS/MS. Patients filled out a questionnaire on hair treatments and washing habits. In parallel, tacrolimus trough levels were measured in whole blood and correlated with hair tacrolimus concentrations.ResultsIn total, 39 consenting KT recipients were included, and hair samples were collected at 53 visits. Tacrolimus was detected in 98% of hair samples from patients exposed to the drug. Tacrolimus hair levels and whole blood trough levels were correlated with a beta coefficient of 0.42 (95% CI: -0.22-1.1, p = n.s.). Age and dark hair affected hair tacrolimus measurements, while different tacrolimus formulations (immediate release vs. extended release), hair washes, and permanent coloring did not. Longitudinal measurements in a subgroup of patients indicate that long-term measurement of hair tacrolimus levels is feasible.ConclusionMeasuring tacrolimus in hair is a potentially reliable method to monitor drug exposure in KT patients. Rapid wash-in effects and consistent concentrations over time indicate that tacrolimus is incorporated into the hair matrix, allowing temporal resolution in the analysis of recent exposure and exposure history. This method provides a simple and low-risk alternative to regular blood sampling, sparing patients from frequent hospital visits through the self-collection of hair samples.