Should we abandon therapeutic drug monitoring of tacrolimus in whole blood and move to intracellular concentration measurements?

Abstract

The measurement of whole blood (WB) concentrations has been the primary method for therapeutic drug monitoring (TDM) of tacrolimus since its introduction in the field of organ transplantation. However, more than 99% of tacrolimus measured in WB is bound to erythrocytes and plasma proteins, which are the pharmacologically inactive fractions. The pharmacologically active fractions, the free (or unbound) tacrolimus in plasma and the intracellular tacrolimus, make up 1% or less of the WB concentration. The mechanism of action of tacrolimus is to inhibit the enzyme calcineurin within T lymphocytes, and therefore, measuring the intra‐lymphocytic tacrolimus concentration may better reflect its pharmacodynamic effects and better correlate with clinical outcomes. However, studies on intracellular tacrolimus concentrations have shown conflicting results. In this review, we argue that we need to overcome the analytical limitations of current assays for the measurement of intracellular tacrolimus before moving this technique into the clinical setting. The validity and standardization of the cell isolation process before the measurement of the intracellular tacrolimus concentration is as important as the measurement itself but has received little attention in our view. Recent evidence suggests that the addition of an inhibitor of P‐glycoprotein, an efflux transporter expressed on lymphocytes, prevents the expulsion of tacrolimus during the cell isolation process. Refining the technique for the intracellular tacrolimus concentration measurement should be the focus followed by clinical evaluation of its association with rejection risk.

The use of extended-release tacrolimus twice a day might be beneficial for selected kidney transplant recipients: a case report

“…Other considerations in therapeutic drug monitoring include measuring tacrolimus concentrations in intracellular rather than whole blood. This is because most of the tacrolimus measured in whole blood is bound to erythrocytes and plasma proteins and thus represents the pharmacologically inactive fraction ( 17 ).…”