Immunomonitoring of Tacrolimus in Healthy Volunteers: The First Step from PK- to PD-Based Therapeutic Drug Monitoring?

Abstract

Therapeutic drug monitoring is routinely performed to maintain optimal tacrolimus concentrations in kidney transplant recipients. Nonetheless, toxicity and rejection still occur within an acceptable concentration-range. To have a better understanding of the relationship between tacrolimus dose, tacrolimus concentration, and its effect on the target cell, we developed functional immune tests for the quantification of the tacrolimus effect. Twelve healthy volunteers received a single dose of tacrolimus, after which intracellular and whole blood tacrolimus concentrations were measured and were related to T cell functionality. A significant correlation was found between tacrolimus concentrations in T cells and whole blood concentrations (r = 0.71, p = 0.009), while no correlation was found between tacrolimus concentrations in peripheral blood mononuclear cells (PBMCs) and whole blood (r = 0.35, p = 0.27). Phytohemagglutinin (PHA) induced the production of IL-2 and IFNγ, as well as the inhibition of CD71 and CD154 expression on T cells at 1.5 h post-dose, when maximum tacrolimus levels were observed. Moreover, the in vitro tacrolimus effect of the mentioned markers corresponded with the ex vivo effect after dosing. In conclusion, our results showed that intracellular tacrolimus concentrations mimic whole blood concentrations, and that PHA-induced cytokine production (IL-2 and IFNγ) and activation marker expression (CD71 and CD154) are suitable readout measures to measure the immunosuppressive effect of tacrolimus on the T cell.

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

“…Finally, it is possible that both whole‐blood and intracellular tacrolimus concentrations are not the right matrix for monitoring tacrolimus exposure. Future studies may also focus on other matrices to monitor tacrolimus treatment, which might have a stronger correlation with clinical outcomes, such as for example, the T lymphocyte subset of PBMCs or the unbound (or free) tacrolimus concentrations 2,46–48 …”

Association Between the Intracellular Tacrolimus Concentration in CD3+ T Lymphocytes and CD14+ Monocytes and Acute Kidney Transplant Rejection

“…This is in line with previous studies that reported a poor correlation between TAC [PBMC] and whole-blood C 0 . [6][7][8][9][10][20][21][22] The poor correlation between whole-blood C 0 and intracellular tacrolimus concentrations emphasizes the importance of measuring tacrolimus concentration in its target compartment(s), as the latter cannot be extrapolated from whole-blood concentration.…”

“…time of transplantation, % (median, Q1-Q3) 0 (0-4) Time from transplantation to kidney biopsy, days (median, Q1-Q3) 9(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) ESRD, end-stage renal disease; HLA, human leukocyte antigen; PRA, panel reactive antibody.…”

Ex vivo generation of regulatory T cells from liver transplant recipients using costimulation blockade

“…Many animal models and in vitro studies describe IST effects, but few studies detail effects of in vivo chronic posttransplant IST exposure on human PBMC 3,32,46,50,54,55,72‐75 57–64 …”