Florian Lemaitre1, Benoit Blanchet2, Marianne Latournerie3, Marie Antignac4, Pauline Houssel-Debry3, Marie-Clémence Verdier5, Marine Dermu5, Christophe Camus6, Jérome Le Priol7, Mikael Roussel7, Yi Zheng2, Pierre Fillatre8, Emmanuel Curis9, Eric Bellissant5, Karim Boudjema10, Christine Fernandez4. 1. Rennes University Hospital, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Centre, Rennes, France; Rennes 1 University, Faculty of Medicine, Laboratory of Experimental and Clinical Pharmacology, Rennes, France; Inserm, CIC-P 1414 Clinical Investigation Centre, Rennes, France; Paris Sud University, Faculty of Pharmacy, EA4123 Barrières physiologiques et réponses thérapeutiques, Châtenay-Malabry, France. Electronic address: florian.lemaitre@chu-rennes.fr. 2. Cochin Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Pharmacokinetics and pharmacochemistry Department, Paris, France. 3. Inserm, CIC-P 1414 Clinical Investigation Centre, Rennes, France; Rennes University Hospital, Liver Disease Unit, Rennes, France. 4. Paris Sud University, Faculty of Pharmacy, EA4123 Barrières physiologiques et réponses thérapeutiques, Châtenay-Malabry, France; Saint-Antoine Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Pharmacy Department, Paris, France. 5. Rennes University Hospital, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Centre, Rennes, France; Rennes 1 University, Faculty of Medicine, Laboratory of Experimental and Clinical Pharmacology, Rennes, France; Inserm, CIC-P 1414 Clinical Investigation Centre, Rennes, France. 6. Inserm, CIC-P 1414 Clinical Investigation Centre, Rennes, France; Rennes University Hospital, Intensive Care Medicine Unit, Rennes, France. 7. Rennes University Hospital, Haematology Department, Rennes, France. 8. Rennes University Hospital, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Centre, Rennes, France; Rennes 1 University, Faculty of Medicine, Laboratory of Experimental and Clinical Pharmacology, Rennes, France; Inserm, CIC-P 1414 Clinical Investigation Centre, Rennes, France; Rennes University Hospital, Intensive Care Medicine Unit, Rennes, France. 9. Paris Descartes, Sorbonne Paris Cité University, Faculty of Pharmacy, Biomathematics Laboratory, Paris, France; Inserm, Paris Descartes University, Paris Diderot University, UMR-S 1144, Paris, France. 10. Inserm, CIC-P 1414 Clinical Investigation Centre, Rennes, France; Rennes University Hospital, Department of Hepatobiliary and Digestive Surgery, Rennes, France.
Abstract
OBJECTIVES: Despite improvements in patient management and extensive use of therapeutic drug monitoring (TDM), the rate of acute cellular rejection (ACR) remains high in patients treated with tacrolimus (TAC). Moreover, some patients experienced ACR while their whole-blood (WB) concentrations were maintained within the therapeutic range meaning that TDM in WB misrepresents the drug effect. Thus, monitoring TAC directly inside of its effect compartment (intracellular concentrations) or monitoring directly the inhibitory effect on the target protein (calcineurin activity) could be more relevant. The aim of the present study was to explore, in 10 de novo liver transplant recipients, the relationship between TAC whole-blood concentrations, TAC intracellular concentrations and TAC-induced intracellular calcineurin inhibition at day 1 and day 7 after treatment initiation. DESIGN AND METHODS: Prospective monocentric observational pharmacokinetic (WB and intracellular concentrations)-pharmacodynamic (calcineurin activity) study. RESULTS: Full intracellular TAC pharmacokinetic as well as calcineurin activity steady-state profiles is presented in the study. The main result of this study is the lack of relationship between TAC pharmacokinetics (WB and leukocytes) and calcineurin activity in leukocytes at day 1 and day 7 after the graft implantation. CONCLUSIONS: Drug monitoring of TAC intracellular concentrations and determination of the calcineurin activity are among future potential biomarkers of acute rejection in transplant recipients. A better knowledge of the relationship between TAC whole blood and intracellular concentrations and calcineurin activity appears necessary before planning clinical trials to evaluate their potential interest as predictive biomarkers.
OBJECTIVES: Despite improvements in patient management and extensive use of therapeutic drug monitoring (TDM), the rate of acute cellular rejection (ACR) remains high in patients treated with tacrolimus (TAC). Moreover, some patients experienced ACR while their whole-blood (WB) concentrations were maintained within the therapeutic range meaning that TDM in WB misrepresents the drug effect. Thus, monitoring TAC directly inside of its effect compartment (intracellular concentrations) or monitoring directly the inhibitory effect on the target protein (calcineurin activity) could be more relevant. The aim of the present study was to explore, in 10 de novo liver transplant recipients, the relationship between TAC whole-blood concentrations, TAC intracellular concentrations and TAC-induced intracellular calcineurin inhibition at day 1 and day 7 after treatment initiation. DESIGN AND METHODS: Prospective monocentric observational pharmacokinetic (WB and intracellular concentrations)-pharmacodynamic (calcineurin activity) study. RESULTS: Full intracellular TAC pharmacokinetic as well as calcineurin activity steady-state profiles is presented in the study. The main result of this study is the lack of relationship between TAC pharmacokinetics (WB and leukocytes) and calcineurin activity in leukocytes at day 1 and day 7 after the graft implantation. CONCLUSIONS: Drug monitoring of TAC intracellular concentrations and determination of the calcineurin activity are among future potential biomarkers of acute rejection in transplant recipients. A better knowledge of the relationship between TAC whole blood and intracellular concentrations and calcineurin activity appears necessary before planning clinical trials to evaluate their potential interest as predictive biomarkers.
Authors: Ida Robertsen; Jean Debord; Anders Åsberg; Pierre Marquet; Jean-Baptiste Woillard Journal: Clin Pharmacokinet Date: 2018-11 Impact factor: 6.447
Authors: Pere Fontova; Helena Colom; Raül Rigo-Bonnin; Lisanne N van Merendonk; Anna Vidal-Alabró; Nuria Montero; Edoardo Melilli; Maria Meneghini; Anna Manonelles; Josep M Cruzado; Juan Torras; Josep Maria Grinyó; Oriol Bestard; Nuria Lloberas Journal: Front Pharmacol Date: 2021-03-17 Impact factor: 5.810
Authors: Maaike A Sikma; Claudine C Hunault; Alwin D R Huitema; Dylan W De Lange; Erik M Van Maarseveen Journal: Clin Pharmacokinet Date: 2020-04 Impact factor: 6.447
Authors: Aliede E In 't Veld; Hendrika W Grievink; Mahdi Saghari; Frederik E Stuurman; Marieke L de Kam; Aiko P J de Vries; Brenda C M de Winter; Jacobus Burggraaf; Adam F Cohen; Matthijs Moerland Journal: Int J Mol Sci Date: 2019-09-23 Impact factor: 5.923
Authors: Marith I Francke; Dennis A Hesselink; Yi Li; Birgit C P Koch; Lucia E A de Wit; Ron H N van Schaik; Lin Yang; Carla C Baan; Teun van Gelder; Brenda C M de Winter Journal: Br J Clin Pharmacol Date: 2020-11-24 Impact factor: 4.335