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Clinical Trial
. 2020 Jun;59(6):771-780.
doi: 10.1007/s40262-019-00854-1.

Unbound Plasma, Total Plasma, and Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

Maaike A Sikma  1   2 , Erik M Van Maarseveen  3 , Claudine C Hunault  4 , Javier M Moreno  5 , Ed A Van de Graaf  6 , Johannes H Kirkels  7 , Marianne C Verhaar  8 , Jan C Grutters  6   9 , Jozef Kesecioglu  10 , Dylan W De Lange  11   10 , Alwin D R Huitema  3   12
Affiliations
Clinical Trial

Unbound Plasma, Total Plasma, and Whole-Blood Tacrolimus Pharmacokinetics Early After Thoracic Organ Transplantation

Maaike A Sikma et al. Clin Pharmacokinet. 2020 Jun.

Erratum in

Abstract

Background and objective: Therapeutic drug monitoring of tacrolimus whole-blood concentrations is standard care in thoracic organ transplantation. Nevertheless, toxicity may appear with alleged therapeutic concentrations possibly related to variability in unbound concentrations. However, pharmacokinetic data on unbound concentrations are not available. The objective of this study was to quantify the pharmacokinetics of whole-blood, total, and unbound plasma tacrolimus in patients early after heart and lung transplantation.

Methods: Twelve-hour tacrolimus whole-blood, total, and unbound plasma concentrations of 30 thoracic organ recipients were analyzed with high-performance liquid chromatography-tandem mass spectrometry directly after transplantation. Pharmacokinetic modeling was performed using non-linear mixed-effects modeling.

Results: Plasma concentration was < 1% of the whole-blood concentration. Maximum binding capacity of erythrocytes was directly proportional to hematocrit and estimated at 2700 pg/mL (95% confidence interval 1750-3835) with a dissociation constant of 0.142 pg/mL (95% confidence interval 0.087-0.195). The inter-individual variability in the binding constants was considerable (27% maximum binding capacity, and 29% for the linear binding constant of plasma).

Conclusions: Tacrolimus association with erythrocytes was high and suggested a non-linear distribution at high concentrations. Monitoring hematocrit-corrected whole-blood tacrolimus concentrations might improve clinical outcomes in clinically unstable thoracic organ transplants.

Clinical trial registration: NTR 3912/EudraCT 2012-001909-24.

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Conflict of interest statement

Jozef Kesecioglu reports personal fees from an honorarium received from Xenios AG, outside the submitted work. Maaike A. Sikma, Erik M. Van Maarseveen, Claudine C. Hunault, Javier M. Moreno, Ed A. Van de Graaf, Johannes H. Kirkels, Marianne C. Verhaar, Jan C. Grutters, Dylan W. De Lange, and Alwin D.R. Huitema have no conflicts of interest that are directly relevant to the content of this study.

Figures

Fig. 1
Fig. 1
Goodness-of-fit plots of predicted unbound tacrolimus plasma concentrations
Fig. 2
Fig. 2
a Tacrolimus unbound plasma concentrations (UPC) vs. tacrolimus whole-blood concentrations (WBC). The figure shows a non-linear relationship between UPC and WBC. b UPC vs tacrolimus total plasma concentrations (TPC). The figure shows a linear relationship between UPC and TPC
Fig. 3
Fig. 3
Schematic representation of the population-pharmacokinetic whole-blood concentration (WBC) model for tacrolimus. The central compartment, with volume V1, is swiftly in equilibrium with the peripheral compartment represented by volume V2. Drug transfer between this peripheral compartment and the central compartment is described with the inter-compartmental clearance parameter Q. ka is the absorption rate constant and CL is the whole-blood tacrolimus clearance. The unbound plasma concentration of tacrolimus (UPC) was computed using a non-linear model, as follows: UPC = (WBC × kd1)/(Bmax × Ht − WBC), where kd1 is the dissociation constant (fitted parameter), Bmax is the maximum binding capacity (fitted parameter), and Ht is the observed hematocrit (last observation carried forward). The total plasma concentration (TPC) was computed using a linear model, as follows: TPC Nplasma × UPC with Nplasma non-specific binding constant for total plasma concentrations (fitted parameter)
Fig. 4
Fig. 4
Simulations of different hematocrit values with a fixed whole-blood concentration of 9 ng/mL. On the y-axis, the unbound tacrolimus plasma concentrations are plotted against hematocrit
See this image and copyright information in PMC

References

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