Dataset Information

A Joint Pharmacokinetic Model for the Simultaneous Description of Plasma and Whole Blood Tacrolimus Concentrations in Kidney and Lung Transplant Recipients.

ABSTRACT:

Background and objective

Historically, dosing of tacrolimus is guided by therapeutic drug monitoring (TDM) of the whole blood concentration, which is strongly influenced by haematocrit. The therapeutic and adverse effects are however expected to be driven by the unbound exposure, which could be better represented by measuring plasma concentrations.

Objective

We aimed to establish plasma concentration ranges reflecting whole blood concentrations within currently used target ranges.

Methods

Plasma and whole blood tacrolimus concentrations were determined in samples of transplant recipients included in the TransplantLines Biobank and Cohort Study. Targeted whole blood trough concentrations are 4-6 ng/mL and 7-10 ng/mL for kidney and lung transplant recipients, respectively. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. Simulations were performed to infer plasma concentration ranges corresponding to whole blood target ranges.

Results

Plasma (n = 1973) and whole blood (n = 1961) tacrolimus concentrations were determined in 1060 transplant recipients. A one-compartment model with fixed first-order absorption and estimated first-order elimination characterised observed plasma concentrations. Plasma was linked to whole blood using a saturable binding equation (maximum binding 35.7 ng/mL, 95% confidence interval (CI) 31.0-40.4 ng/mL; dissociation constant 0.24 ng/mL, 95% CI 0.19-0.29 ng/mL). Model simulations indicate that patients within the whole blood target range are expected to have plasma concentrations (95% prediction interval) of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively.

Conclusion

Whole blood tacrolimus target ranges, currently used to guide TDM, were translated to plasma concentration ranges of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively.

SUBMITTER: Koomen JV

PROVIDER: S-EPMC10386913 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

A Joint Pharmacokinetic Model for the Simultaneous Description of Plasma and Whole Blood Tacrolimus Concentrations in Kidney and Lung Transplant Recipients.

Koomen Jeroen V JV Knobbe Tim J TJ Zijp Tanja R TR Kremer Daan D Gan C Tji CT Verschuuren Erik A M EAM Bakker Stephan J L SJL Touw Daan J DJ Colin Pieter J PJ

Clinical pharmacokinetics 20230612 8

<h4>Background and objective</h4>Historically, dosing of tacrolimus is guided by therapeutic drug monitoring (TDM) of the whole blood concentration, which is strongly influenced by haematocrit. The therapeutic and adverse effects are however expected to be driven by the unbound exposure, which could be better represented by measuring plasma concentrations.<h4>Objective</h4>We aimed to establish plasma concentration ranges reflecting whole blood concentrations within currently used target ranges. ...[more]

PMID: 37306899

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Project description:Background and objectiveThe 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.MethodsPharmacokinetic 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.ResultsA 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.ConclusionWe 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.

Dataset Information

A Joint Pharmacokinetic Model for the Simultaneous Description of Plasma and Whole Blood Tacrolimus Concentrations in Kidney and Lung Transplant Recipients.

Background and objective

Objective

Methods

Results

Conclusion

Publications

A Joint Pharmacokinetic Model for the Simultaneous Description of Plasma and Whole Blood Tacrolimus Concentrations in Kidney and Lung Transplant Recipients.

Similar Datasets

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