title: Pharmacokinetics and pharmacodynamics of tacrolimus in liver transplant recipients: inside the white blood cells.
abstract: OBJECTIVE
  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.
  
  
  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.affiliation: 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.
authors.forename: Florian
authors.initials: F
authors.lastname: Lemaitre
authors.affiliation: Cochin Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Pharmacokinetics and pharmacochemistry Department, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Blanchet
authors.affiliation: Inserm, CIC-P 1414 Clinical Investigation Centre, Rennes, France; Rennes University Hospital, Liver Disease Unit, Rennes, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Latournerie
authors.affiliation: 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.
authors.forename: Marie
authors.initials: M
authors.lastname: Antignac
authors.affiliation: Inserm, CIC-P 1414 Clinical Investigation Centre, Rennes, France; Rennes University Hospital, Liver Disease Unit, Rennes, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Houssel-Debry
authors.affiliation: 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.
authors.forename: Marie-Clémence
authors.initials: MC
authors.lastname: Verdier
authors.affiliation: 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.
authors.forename: Marine
authors.initials: M
authors.lastname: Dermu
authors.affiliation: Inserm, CIC-P 1414 Clinical Investigation Centre, Rennes, France; Rennes University Hospital, Intensive Care Medicine Unit, Rennes, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Camus
authors.affiliation: Rennes University Hospital, Haematology Department, Rennes, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Le Priol
authors.affiliation: Rennes University Hospital, Haematology Department, Rennes, France.
authors.forename: Mikael
authors.initials: M
authors.lastname: Roussel
authors.affiliation: Cochin Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Pharmacokinetics and pharmacochemistry Department, Paris, France.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fillatre
authors.affiliation: 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.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Curis
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Bellissant
authors.affiliation: Inserm, CIC-P 1414 Clinical Investigation Centre, Rennes, France; Rennes University Hospital, Department of Hepatobiliary and Digestive Surgery, Rennes, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Boudjema
authors.affiliation: 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.
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandez
mesh_terms: D000368:Aged; D019540:Area Under Curve; D019703:Calcineurin / Q000378:metabolism; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000601:surgery*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016559:Tacrolimus / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D019703:Calcineurin; D016559:Tacrolimus
keywords: Calcineurin; Immunosuppressive drugs; Intracellular; Peripheral blood mononuclear cells; Therapeutic drug monitoring