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.
Highlights
A combination of tacrolimus, mycophenolate mofetil (MMF), and glucocorticoids is the standard treatment of choice for kidney transplant recipients
Despite routinely performed therapeutic drug monitoring (TDM) in kidney transplant recipients, transplant rejection, infection, andtoxicity are still prevalent among patients with tacrolimus concentrations within the target range
Tacrolimus concentrations were quantified in whole blood, peripheral blood mononuclear cells (PBMCs), and T cells, and correlated with proximal drug effects
Summary
A combination of tacrolimus, mycophenolate mofetil (MMF), and glucocorticoids is the standard treatment of choice for kidney transplant recipients. Calcineurin inhibitors (CNIs), like tacrolimus, suffer from large intra- and inter-patient variability in pharmacodynamic (PD) activity, complicating optimization of an individual dosing strategy [3]. The calcineurin inhibitor tacrolimus (FK506) is generally used after allogeneic organ transplantation, and in other T cell-mediated diseases such as eczema and psoriasis. In order to maintain optimal levels of tacrolimus and to minimize the risk of overexposure, therapeutic drug monitoring (TDM) of pre-dose trough levels (C0) in whole blood is routinely performed in kidney transplant recipients. The monitoring of intracellular drug concentrations in peripheral blood mononuclear cells (PBMCs) can be informative, its correlation with clinical outcomes is suboptimal [6]
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