Dataset Information

Adaptation of a population pharmacokinetic model to inform tacrolimus therapy in heart transplant recipients.

ABSTRACT:

Aim

Existing tacrolimus population pharmacokinetic models are unsuitable for guiding tacrolimus dosing in heart transplant recipients. This study aimed to develop and evaluate a population pharmacokinetic model for tacrolimus in heart transplant recipients that considers the tacrolimus-azole antifungal interaction.

Methods

Data from heart transplant recipients (n = 87) administered the oral immediate-release formulation of tacrolimus (Prograf®) were collected. Routine drug monitoring data, principally trough concentrations, were used for model building (n = 1099). A published tacrolimus model was used to inform the estimation of K_a , V₂ /F, Q/F and V₃ /F. The effect of concomitant azole antifungal use on tacrolimus CL/F was quantified. Fat-free mass was implemented as a covariate on CL/F, V₂ /F, V₃ /F and Q/F on an allometry scale. Subsequently, stepwise covariate modelling was performed. Significant covariates influencing tacrolimus CL/F were included in the final model. Robustness of the final model was confirmed using prediction-corrected visual predictive check (pcVPC). The final model was externally evaluated for prediction of tacrolimus concentrations of the fourth dosing occasion (n = 87) from one to three prior dosing occasions.

Results

Concomitant azole antifungal therapy reduced tacrolimus CL/F by 80%. Haematocrit (∆OFV = -44, P < .001) was included in the final model. The pcVPC of the final model displayed good model adequacy. One recent drug concentration is sufficient for the model to guide tacrolimus dosing.

Conclusion

A population pharmacokinetic model that adequately describes tacrolimus pharmacokinetics in heart transplant recipients, considering the tacrolimus-azole antifungal interaction was developed. Prospective evaluation is required to assess its clinical utility to improve patient outcomes.

SUBMITTER: Kirubakaran R

PROVIDER: S-EPMC10952588 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Adaptation of a population pharmacokinetic model to inform tacrolimus therapy in heart transplant recipients.

Kirubakaran Ranita R Uster David W DW Hennig Stefanie S Carland Jane E JE Day Richard O RO Wicha Sebastian G SG Stocker Sophie L SL

British journal of clinical pharmacology 20221106 3

<h4>Aim</h4>Existing tacrolimus population pharmacokinetic models are unsuitable for guiding tacrolimus dosing in heart transplant recipients. This study aimed to develop and evaluate a population pharmacokinetic model for tacrolimus in heart transplant recipients that considers the tacrolimus-azole antifungal interaction.<h4>Methods</h4>Data from heart transplant recipients (n = 87) administered the oral immediate-release formulation of tacrolimus (Prograf®) were collected. Routine drug monitor ...[more]

PMID: 36239542

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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

Adaptation of a population pharmacokinetic model to inform tacrolimus therapy in heart transplant recipients.

Aim

Methods

Results

Conclusion

Publications

Adaptation of a population pharmacokinetic model to inform tacrolimus therapy in heart transplant recipients.

Similar Datasets

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