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

Authors :
Pere Fontova
Lisanne N. van Merendonk
Anna Vidal-Alabró
Raül Rigo-Bonnin
Gema Cerezo
Stefaan van Oevelen
Oriol Bestard
Edoardo Melilli
Nuria Montero
Ana Coloma
Anna Manonelles
Joan Torras
Josep M. Cruzado
Josep M. Grinyó
Helena Colom
Nuria Lloberas
Source :
Pharmaceutics, Vol 15, Iss 5, p 1481 (2023)
Publication Year :
2023
Publisher :
MDPI AG, 2023.

Abstract

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 (C0 and C24) and total exposure (AUC0–24) values were found for TAC-LCP than TAC-IR. Lower intracellular peak concentration (Cmax) was found after TAC-LCP. Correlations between C0, C24 and AUC0–24 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 IC50, a concentration to achieve 50% CNA inhibition, of 43.9 pg/million cells.

Details

Language :
English
ISSN :
19994923
Volume :
15
Issue :
5
Database :
Directory of Open Access Journals
Journal :
Pharmaceutics
Publication Type :
Academic Journal
Accession number :
edsdoj.17151f14f7b844a0abfe1718be0a1db2
Document Type :
article
Full Text :
https://doi.org/10.3390/pharmaceutics15051481