Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients

Tacrolimus (TAC) is a first-choice immunosuppressant for solid organ transplantation, characterized by high potential for drug-drug interactions, significant inter- and intra-patient variability, and narrow therapeutic index. Therapeutic drug monitoring (TDM) of TAC concentrations in whole blood (WB...

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Autores principales:	Amedeo De Nicolò, Michele Pinon, Alice Palermiti, Antonello Nonnato, Alessandra Manca, Jacopo Mula, Silvia Catalano, Francesco Tandoi, Renato Romagnoli, Antonio D’Avolio, Pier Luigi Calvo
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	pharmacokinetics immunosuppressant pharmacology pharmacokinetics-pharmacodynamics transplantation pharmacokinectics Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/60763e1cd80049c3a0135c3381f099e7
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spelling	oai:doaj.org-article:60763e1cd80049c3a0135c3381f099e72021-11-05T14:29:21ZMonitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients1663-981210.3389/fphar.2021.750433https://doaj.org/article/60763e1cd80049c3a0135c3381f099e72021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.750433/fullhttps://doaj.org/toc/1663-9812Tacrolimus (TAC) is a first-choice immunosuppressant for solid organ transplantation, characterized by high potential for drug-drug interactions, significant inter- and intra-patient variability, and narrow therapeutic index. Therapeutic drug monitoring (TDM) of TAC concentrations in whole blood (WB) is capable of reducing the incidence of adverse events. Since TAC acts within lymphocytes, its monitoring in peripheral blood mononuclear cells (PBMC) may represent a valid future alternative for TDM. Nevertheless, TAC intracellular concentrations and their variability are poorly described, particularly in the pediatric context. Therefore, our aim was describing TAC concentrations in WB and PBMC and their variability in a cohort of pediatric patients undergoing constant immunosuppressive maintenance therapy, after liver transplantation. TAC intra-PBMCs quantification was performed through a validated UHPLC–MS/MS assay over a period of 2–3 months. There were 27 patients included in this study. No significant TAC changes in intracellular concentrations were observed (p = 0.710), with a median percent change of −0.1% (IQR −22.4%–+46.9%) between timings: this intra-individual variability was similar to the one in WB, −2.9% (IQR −29.4–+42.1; p = 0.902). Among different patients, TAC weight-adjusted dose and age appeared to be significant predictors of TAC concentrations in WB and PBMC. Intra-individual seasonal variation of TAC concentrations in WB, but not in PBMC, have been observed. These data show that the intra-individual variability in TAC intracellular exposure is comparable to the one observed in WB. This opens the way for further studies aiming at the identification of therapeutic ranges for TAC intra-PBMC concentrations.Amedeo De NicolòMichele PinonAlice PalermitiAntonello NonnatoAlessandra MancaJacopo MulaSilvia CatalanoFrancesco TandoiRenato RomagnoliAntonio D’AvolioPier Luigi CalvoFrontiers Media S.A.articlepharmacokineticsimmunosuppressantpharmacologypharmacokinetics-pharmacodynamicstransplantationpharmacokinecticsTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pharmacokinetics immunosuppressant pharmacology pharmacokinetics-pharmacodynamics transplantation pharmacokinectics Therapeutics. Pharmacology RM1-950
spellingShingle	pharmacokinetics immunosuppressant pharmacology pharmacokinetics-pharmacodynamics transplantation pharmacokinectics Therapeutics. Pharmacology RM1-950 Amedeo De Nicolò Michele Pinon Alice Palermiti Antonello Nonnato Alessandra Manca Jacopo Mula Silvia Catalano Francesco Tandoi Renato Romagnoli Antonio D’Avolio Pier Luigi Calvo Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients
description	Tacrolimus (TAC) is a first-choice immunosuppressant for solid organ transplantation, characterized by high potential for drug-drug interactions, significant inter- and intra-patient variability, and narrow therapeutic index. Therapeutic drug monitoring (TDM) of TAC concentrations in whole blood (WB) is capable of reducing the incidence of adverse events. Since TAC acts within lymphocytes, its monitoring in peripheral blood mononuclear cells (PBMC) may represent a valid future alternative for TDM. Nevertheless, TAC intracellular concentrations and their variability are poorly described, particularly in the pediatric context. Therefore, our aim was describing TAC concentrations in WB and PBMC and their variability in a cohort of pediatric patients undergoing constant immunosuppressive maintenance therapy, after liver transplantation. TAC intra-PBMCs quantification was performed through a validated UHPLC–MS/MS assay over a period of 2–3 months. There were 27 patients included in this study. No significant TAC changes in intracellular concentrations were observed (p = 0.710), with a median percent change of −0.1% (IQR −22.4%–+46.9%) between timings: this intra-individual variability was similar to the one in WB, −2.9% (IQR −29.4–+42.1; p = 0.902). Among different patients, TAC weight-adjusted dose and age appeared to be significant predictors of TAC concentrations in WB and PBMC. Intra-individual seasonal variation of TAC concentrations in WB, but not in PBMC, have been observed. These data show that the intra-individual variability in TAC intracellular exposure is comparable to the one observed in WB. This opens the way for further studies aiming at the identification of therapeutic ranges for TAC intra-PBMC concentrations.
format	article
author	Amedeo De Nicolò Michele Pinon Alice Palermiti Antonello Nonnato Alessandra Manca Jacopo Mula Silvia Catalano Francesco Tandoi Renato Romagnoli Antonio D’Avolio Pier Luigi Calvo
author_facet	Amedeo De Nicolò Michele Pinon Alice Palermiti Antonello Nonnato Alessandra Manca Jacopo Mula Silvia Catalano Francesco Tandoi Renato Romagnoli Antonio D’Avolio Pier Luigi Calvo
author_sort	Amedeo De Nicolò
title	Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients
title_short	Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients
title_full	Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients
title_fullStr	Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients
title_full_unstemmed	Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients
title_sort	monitoring tacrolimus concentrations in whole blood and peripheral blood mononuclear cells: inter- and intra-patient variability in a cohort of pediatric patients
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/60763e1cd80049c3a0135c3381f099e7
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Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients

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