The Effect of Intracellular Tacrolimus Exposure on Calcineurin Inhibition in Immediate- and Extended-Release Tacrolimus Formulations

Despite intensive monitoring of whole blood tacrolimus concentrations, acute rejection after kidney transplantation occurs during tacrolimus therapy. Intracellular tacrolimus concentrations could better reflect exposure at the site of action and its pharmacodynamics (PD). Intracellular pharmacokinet...

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Published in:Pharmaceutics 2023-05, Vol.15 (5), p.1481
Main Authors: Fontova, Pere, van Merendonk, Lisanne N, Vidal-Alabró, Anna, Rigo-Bonnin, Raül, Cerezo, Gema, van Oevelen, Stefaan, Bestard, Oriol, Melilli, Edoardo, Montero, Nuria, Coloma, Ana, Manonelles, Anna, Torras, Joan, Cruzado, Josep M, Grinyó, Josep M, Colom, Helena, Lloberas, Nuria
Format: Article
Language:English
Subjects:
Drug dosages
kidney transplantation
leukocytes
mononuclear
Parameter estimation
Peptides
Pharmacodynamics
Pharmacokinetics
Tacrolimus
Transplants & implants
Variables
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Summary:Despite intensive monitoring of whole blood tacrolimus concentrations, acute rejection after kidney transplantation occurs during tacrolimus therapy. Intracellular tacrolimus concentrations could better reflect exposure at the site of action and its pharmacodynamics (PD). Intracellular pharmacokinetic (PK) profile following different tacrolimus formulations (immediate-release (TAC-IR) and extended-release (TAC-LCP)) remains unclear. Therefore, the aim was to study intracellular tacrolimus PK of TAC-IR and TAC-LCP and its correlation with whole blood (WhB) PK and PD. A post-hoc analysis of a prospective, open-label, crossover investigator-driven clinical trial (NCT02961608) was performed. Intracellular and WhB tacrolimus 24 h time-concentration curves were measured in 23 stable kidney transplant recipients. PD analysis was evaluated measuring calcineurin activity (CNA) and simultaneous intracellular PK/PD modelling analysis was conducted. Higher dose-adjusted pre-dose intracellular concentrations (C and C ) and total exposure (AUC ) values were found for TAC-LCP than TAC-IR. Lower intracellular peak concentration (C ) was found after TAC-LCP. Correlations between C , C and AUC were observed within both formulations. Intracellular kinetics seems to be limited by WhB disposition, in turn, limited by tacrolimus release/absorption processes from both formulations. The faster intracellular elimination after TAC-IR was translated into a more rapid recovery of CNA. An Emax model relating % inhibition and intracellular concentrations, including both formulations, showed an IC , a concentration to achieve 50% CNA inhibition, of 43.9 pg/million cells.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics15051481