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. 2022 Jul;47(4):523-535.
doi: 10.1007/s13318-022-00767-8. Epub 2022 Apr 20.

A Population Pharmacokinetic Model of Whole-Blood and Intracellular Tacrolimus in Kidney Transplant Recipients

Linda G Franken #  1 , Marith I Francke #  2   3   4 , Louise M Andrews  1 , Ron H N van Schaik  5 , Yi Li  1   6 , Lucia E A de Wit  1 , Carla C Baan  7   8 , Dennis A Hesselink  7   8 , Brenda C M de Winter  1   9
Affiliations

A Population Pharmacokinetic Model of Whole-Blood and Intracellular Tacrolimus in Kidney Transplant Recipients

Linda G Franken et al. Eur J Drug Metab Pharmacokinet. 2022 Jul.

Abstract

Background and objective: The tacrolimus concentration within peripheral blood mononuclear cells may correlate better with clinical outcomes after transplantation compared to concentrations measured in whole blood. However, intracellular tacrolimus measurements are not easily implemented in clinical practice. The prediction of intracellular concentrations based on whole-blood concentrations would be a solution for this. Therefore, the aim of this study was to describe the relationship between intracellular and whole-blood tacrolimus concentrations in a population pharmacokinetic (popPK) model.

Methods: Pharmacokinetic analysis was performed using non-linear mixed effects modelling software (NONMEM). The final model was evaluated using goodness-of-fit plots, visual predictive checks, and a bootstrap analysis.

Results: A total of 590 tacrolimus concentrations from 184 kidney transplant recipients were included in the study. All tacrolimus concentrations were measured in the first three months after transplantation. The intracellular tacrolimus concentrations (n = 184) were best described with an effect compartment. The distribution into the effect compartment was described by the steady-state whole-blood to intracellular ratio (RWB:IC) and the intracellular distribution rate constant between the whole-blood and intracellular compartments. Lean body weight was negatively correlated [delta objective function value (ΔOFV) -8.395] and haematocrit was positively correlated (ΔOFV = - 6.752) with RWB:IC, and both lean body weight and haematocrit were included in the final model.

Conclusion: We were able to accurately describe intracellular tacrolimus concentrations using whole-blood concentrations, lean body weight, and haematocrit values in a popPK model. This model may be used in the future to more accurately predict clinical outcomes after transplantation and to identify patients at risk for under- and overexposure. Dutch National Trial Registry number NTR2226.

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Conflict of interest statement

D.A. Hesselink has received grant support (paid to his institution) from Astellas Pharma, Chiesi Farmaceutici SpA, and Bristol Myers-Squibb, as well as lecture and consulting fees from Astellas Pharma, Chiesi Farmaceutici SpA, Novartis Pharma, and Vifor Pharma. All other authors declared no competing interests for this work.

Figures

Fig. 1
Fig. 1
Population pharmacokinetic model with intracellular compartment. CL clearance, F bioavailability of oral tacrolimus, Ka absorption rate constant, KWB-IC distribution rate constant, Q inter-compartmental clearance, RWB-IC ratio between whole-blood and intracellular tacrolimus, Tlag lag time, V1 central compartment, V2 peripheral compartment
Fig. 2
Fig. 2
Goodness-of-fit plots of the final model. A Observed intracellular tacrolimus concentrations versus predicted intracellular tacrolimus concentrations. B Observed intracellular tacrolimus concentrations versus the individual predicted intracellular tacrolimus concentrations. C The conditional weighted residuals versus the time after transplantation. D The conditional weighted residuals versus the predicted intracellular tacrolimus concentrations. CWRES conditional weighted residuals
Fig. 3
Fig. 3
Visual predictive checks showing how well the mean observed intracellular tacrolimus concentration (red line) versus the lean body weight (A) and the haematocrit concentration (B) falls within the 95% confidence interval for the predicted mean tacrolimus concentration (red area) and how well the variability of the observed intracellular tacrolimus concentration (red dotted line) falls within the 95% confidence interval for the predicted variability of the intracellular tacrolimus concentration (blue area)
Fig. 4
Fig. 4
Simulations (n  = 1000) of the tacrolimus WB:IC ratio for different haematocrit values (A) and body composition values (B). The box represents the 25th percentile, the median (middle line), and the 75th percentile. The upper whisker reaches to the highest value up to 1.5 times the interquartile range (IQR). The lower whisker reaches to the lowest value up to 1.5 times the IQR. The dots represent the concentrations that lie further away than 1.5 times the IQR. BSA body surface area, LBW lean body weight, IC intracellular, WB whole blood
Fig. 5
Fig. 5
Boxplot of the whole-blood to intracellular tacrolimus concentration ratio for patients with and without biopsy-proven acute rejection (BPAR). The box represents the 25th percentile, the median (middle line), and the 75th percentile. The upper whisker reaches to the highest value up to 1.5 times the interquartile range (IQR). The lower whisker reaches to the lowest value up to 1.5 times the IQR. The dots represent the concentrations that lie further away than 1.5 times the IQR
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