Abstract
(1) Background: Only unbound tacrolimus particles are considered to be active and capable of crossing cellular membranes. Thus, the free-drug concentration might be better associated with clinical effects than the total drug concentration used for dosage adjustment. We propose a new, fully validated online liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for unbound tacrolimus concentration measurement. (2) Methods: The determination of the unbound tacrolimus concentration in plasma ultrafiltrate was performed with the Nexera LC system with LCMS-8050 triple quadrupole MS using ascomycin as an internal standard. Chromatographic separation was made using a HypurityC18 analytical column. MS/MS with electrospray ionization and positive-ion multiple-reaction monitoring was used. The unbound tacrolimus level was determined in 36 patients after solid organ transplantation (n = 140). (3) Results: A lower limit of quantification 0.1 pg/mL was achieved, and the assay was linear between 0.1 and 20 pg/mL (R2 = 0.991). No carry-over was detected. The within-run and between-run accuracies ranged between 97.8–109.7% and 98.3–107.1%, while the greatest imprecision was 10.6% and 10.7%, respectively. Free tacrolimus in patients’ plasma ultrafiltrate varied between 0.06 and 18.25 pg/mL (median: 0.98 pg/mL). (4) Conclusions: The proposed method can be easily implemented. The significance of the unbound tacrolimus concentration needs to be investigated. This may facilitate the individualization and optimization of immunosuppressive treatment.
Highlights
Tacrolimus (TAC) is the first-choice immunosuppressive agent after solid organ transplantation [1,2]
The optimal analytical equipment was chosen for runtime, quality of peak shapes, and possibility of performing separation with the use of a simple mobile phase consisting of two solutions
We propose a new and highly sensitive method for determining unbound TAC
Summary
Tacrolimus (TAC) is the first-choice immunosuppressive agent after solid organ transplantation [1,2]. The safety and efficacy of TAC are well established, drug doses need to be targeted in a narrow therapeutic window. Underexposure may result in acute rejection of the transplanted organ, whereas too high TAC concentrations may lead to TAC toxicity [3–5]. Both increase morbidity and mortality rates in solid organ recipients [1,2,6,7]. TAC-based treatment requires careful therapeutic drug monitoring (TDM) [6]. The TDM of TAC involves whole blood trough concentration (C0 ) measurements to adjust TAC dosage [6]. The golden standard in TAC C0 determination remains liquid chromatography-tandem mass spectrometry (LC-MS/MS) due to its higher sensitivity and
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