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. 2023 Dec;89(12):3584-3595.
doi: 10.1111/bcp.15857. Epub 2023 Aug 10.

Tacrolimus population pharmacokinetics in adult heart transplant patients

Adrien Paschier  1 , Alexandre Destere  2   3   4 , Caroline Monchaud  1   3 , Marc Labriffe  1   3 , Pierre Marquet  1   3 , Jean-Baptiste Woillard  1   3
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Free article

Tacrolimus population pharmacokinetics in adult heart transplant patients

Adrien Paschier et al. Br J Clin Pharmacol. 2023 Dec.
Free article

Abstract

Introduction: Tacrolimus is an immunosuppressant largely used in heart transplantation. However, the calculation of its exposure based on the area under the curve (AUC) requires the use of a population pharmacokinetic (PK) model. The aims of this work were (i) to develop a population PK model for tacrolimus in heart transplant patients, (ii) to derive a maximum a posteriori Bayesian estimator (MAP-BE) based on a limited sampling strategy (LSS) and (iii) to estimate probabilities of target attainment (PTAs) for AUC and trough concentration (C0).

Material and methods: Forty-seven PK profiles (546 concentrations) of 18 heart transplant patients of the Pharmacocinétique des Immunosuppresseurs chez les patients GREffés Cardiaques study receiving tacrolimus (Prograf®) were included. The database was split into a development (80%) and a validation (20%) set. PK parameters were estimated in MONOLIX® and based on this model a Bayesian estimator using an LSS was built. Simulations were performed to calculate the PTA for AUC and C0.

Results: The best model to describe the tacrolimus PK was a two-compartment model with a transit absorption and a linear elimination. Only the CYP3A5 covariate was kept in the final model. The derived MAP-BE based on the LSS (0-1-2 h postdose) yielded an AUC bias ± SD = 2.7 ± 10.2% and an imprecision of 9.9% in comparison to the reference AUC calculated using the trapezoidal rule. PTAs based on AUC or C0 allowed new recommendations to be proposed for starting doses (0.11 mg·kg-1 ·12 h-1 for the CYP3A5 nonexpressor and 0.22 mg·kg1 ·12 h-1 for the CYP3A5 expressor).

Conclusion: The MAP-BE developed should facilitate estimation of tacrolimus AUC in heart transplant patients.

Keywords: Bayesian estimator; heart transplantation; population pharmacokinetic; probability of target attainment; tacrolimus.

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References

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