Monitoring of Tacrolimus Concentration in View of Normalized Indicators and Its Intraindividual Variability in Kidney Transplant Recipients: A Literature Review

INTRODUCTION. Tacrolimus (TAC) in combination with mycophenolate mofetil and glucocorticoids is a cornerstone of immunosuppressive therapy after kidney transplantation. The analytical sensitivity of methods used to determine TAC concentrations in blood samples varies widely and associated with the risk of transplant rejection that requires regular monitoring.

AIM. To evaluate methods for measuring tacrolimus blood concentrations in kidney transplant recipients and compare different approaches to monitoring tacrolimus exposure.

DISCUSSION. Liquid chromatography with mass spectrometry (LC/MS/MS) is the standard for quantitatively assessing TAC in various biomaterials. Immunochemical methods for TAC determination in whole blood have been introduced into clinical practice; however, due to cross-reactivity with inactive TAC metabolites, the results may be overestimating. Immunochemiluminescence method, using magnetic particles, ensures reliable results and allows to determine TAC concentrations down to 0.5 ng/mL, while the coefficient of variation values does not exceed 15% compared to the reference LC/MS/MS method. TAC has a narrow therapeutic window, and its levels in kidney transplant recipients, both in whole blood / plasma and in mononuclear cells, are characterized by high intra-patient variability (IPV). It necessitates the development of new approaches to assessing target TAC levels, including the choice of biomaterial and the method for TAC determination in patients with risk of kidney transplant dysfunction. The most clinically significant marker of immunosuppressive efficacy is the steady-state concentration of TAC in the blood. The C/D ratio has been proposed for toxicity prediction: a decrease in C/D ratio may be a predictor of an unfavorable prognosis due to TAC toxicity in kidney transplant recipients. The IPV directly reflects the stability of drug exposure in a given patient and allows for assessing the risk of transplant rejection and toxicity. A high IPV is an independent predictor of adverse outcomes in kidney transplant recipients. The IPV of TAC concentration depends on endogenous and exogenous factors, such as CYP3A5 polymorphism, dietary factors, drug-drug interactions, and clinical situations. Regular monitoring of IPV and elimination of influencing factors help ensure both immediate and long-term good survival of transplants.

CONCLUSIONS. Tacrolimus has a narrow therapeutic window, and its blood levels in kidney transplant recipients exhibit high IPV. Inter-laboratory comparison and the development of normalized values will minimize variability in TAC concentration assessments, while accounting for IPV will reduce the risk of adverse events during short- and long-term follow-up of kidney transplant recipients. This justifies a revision of approaches to monitoring TAC concentrations to improve treatment outcomes and increase kidney transplant and recipient survival.

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