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Impact of Early Intrapatient Variability of Tacrolimus Concentrations on the Risk of Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide

Tacrolimus (Tac) is a pivotal immunosuppressant agent used to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloHSCT). Tac is characterized by a narrow therapeutic window and a high inter-patient and intra-patient pharmacokinetic variability (IPV). Although hig...

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Autores principales: Marco, Daniel N., Salas, María Queralt, Gutiérrez-García, Gonzalo, Monge, Inés, Riu, Gisela, Carcelero, Esther, Roma, Joan Ramón, Llobet, Noemí, Arcarons, Jordi, Suárez-Lledó, María, Martínez, Nuria, Pedraza, Alexandra, Domenech, Ariadna, Rosiñol, Laura, Fernández-Avilés, Francesc, Urbano-Ispízua, Álvaro, Rovira, Montserrat, Brunet, Mercè, Martínez, Carmen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9784628/
https://www.ncbi.nlm.nih.gov/pubmed/36558980
http://dx.doi.org/10.3390/ph15121529
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author Marco, Daniel N.
Salas, María Queralt
Gutiérrez-García, Gonzalo
Monge, Inés
Riu, Gisela
Carcelero, Esther
Roma, Joan Ramón
Llobet, Noemí
Arcarons, Jordi
Suárez-Lledó, María
Martínez, Nuria
Pedraza, Alexandra
Domenech, Ariadna
Rosiñol, Laura
Fernández-Avilés, Francesc
Urbano-Ispízua, Álvaro
Rovira, Montserrat
Brunet, Mercè
Martínez, Carmen
author_facet Marco, Daniel N.
Salas, María Queralt
Gutiérrez-García, Gonzalo
Monge, Inés
Riu, Gisela
Carcelero, Esther
Roma, Joan Ramón
Llobet, Noemí
Arcarons, Jordi
Suárez-Lledó, María
Martínez, Nuria
Pedraza, Alexandra
Domenech, Ariadna
Rosiñol, Laura
Fernández-Avilés, Francesc
Urbano-Ispízua, Álvaro
Rovira, Montserrat
Brunet, Mercè
Martínez, Carmen
author_sort Marco, Daniel N.
collection PubMed
description Tacrolimus (Tac) is a pivotal immunosuppressant agent used to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloHSCT). Tac is characterized by a narrow therapeutic window and a high inter-patient and intra-patient pharmacokinetic variability (IPV). Although high IPV of Tac concentrations has been associated with adverse post-transplant outcomes following solid organ transplantation, the effects of Tac IPV on alloHSCT recipients have not been determined. Tac IPV was therefore retrospectively evaluated in 128 alloHSCT recipients receiving high-dose post-transplant cyclophosphamide (PTCy) and the effects of Tac IPV on the occurrence of acute GVHD (aGVHD) were analyzed. Tac IPV was calculated from pre-dose concentrations (C(0)) measured during the first month after Tac initiation. The cumulative rates of grades II-IV and grades III-IV aGVHD at day +100 were 22.7% and 7%, respectively. Higher Tac IPV was associated with a greater risk of developing GVHD, with patients having IPV > 50th percentile having significantly higher rates of grades II-IV (34.9% vs. 10.8%; hazard ratio [HR] 3.858, p < 0.001) and grades III-IV (12.7% vs. 1.5%; HR 9.69, p = 0.033) aGVHD than patients having IPV ≤ 50th percentile. Similarly, patients with IPV > 75th percentile had higher rates of grades II-IV (41.9% vs. 16.5%; HR 3.30, p < 0.001) and grades III-IV (16.1% vs. 4.1%; HR 4.99, p = 0.012) aGVHD than patients with IPV ≤ 75th percentile. Multivariate analyses showed that high Tac IPV (>50th percentile) was an independent risk factor for grades II-IV (HR 2.99, p = 0.018) and grades III-IV (HR 9.12, p = 0.047) aGVHD. Determination of Tac IPV soon after alloHSCT could be useful in identifying patients at greater risk of aGVHD.
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spelling pubmed-97846282022-12-24 Impact of Early Intrapatient Variability of Tacrolimus Concentrations on the Risk of Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide Marco, Daniel N. Salas, María Queralt Gutiérrez-García, Gonzalo Monge, Inés Riu, Gisela Carcelero, Esther Roma, Joan Ramón Llobet, Noemí Arcarons, Jordi Suárez-Lledó, María Martínez, Nuria Pedraza, Alexandra Domenech, Ariadna Rosiñol, Laura Fernández-Avilés, Francesc Urbano-Ispízua, Álvaro Rovira, Montserrat Brunet, Mercè Martínez, Carmen Pharmaceuticals (Basel) Article Tacrolimus (Tac) is a pivotal immunosuppressant agent used to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloHSCT). Tac is characterized by a narrow therapeutic window and a high inter-patient and intra-patient pharmacokinetic variability (IPV). Although high IPV of Tac concentrations has been associated with adverse post-transplant outcomes following solid organ transplantation, the effects of Tac IPV on alloHSCT recipients have not been determined. Tac IPV was therefore retrospectively evaluated in 128 alloHSCT recipients receiving high-dose post-transplant cyclophosphamide (PTCy) and the effects of Tac IPV on the occurrence of acute GVHD (aGVHD) were analyzed. Tac IPV was calculated from pre-dose concentrations (C(0)) measured during the first month after Tac initiation. The cumulative rates of grades II-IV and grades III-IV aGVHD at day +100 were 22.7% and 7%, respectively. Higher Tac IPV was associated with a greater risk of developing GVHD, with patients having IPV > 50th percentile having significantly higher rates of grades II-IV (34.9% vs. 10.8%; hazard ratio [HR] 3.858, p < 0.001) and grades III-IV (12.7% vs. 1.5%; HR 9.69, p = 0.033) aGVHD than patients having IPV ≤ 50th percentile. Similarly, patients with IPV > 75th percentile had higher rates of grades II-IV (41.9% vs. 16.5%; HR 3.30, p < 0.001) and grades III-IV (16.1% vs. 4.1%; HR 4.99, p = 0.012) aGVHD than patients with IPV ≤ 75th percentile. Multivariate analyses showed that high Tac IPV (>50th percentile) was an independent risk factor for grades II-IV (HR 2.99, p = 0.018) and grades III-IV (HR 9.12, p = 0.047) aGVHD. Determination of Tac IPV soon after alloHSCT could be useful in identifying patients at greater risk of aGVHD. MDPI 2022-12-09 /pmc/articles/PMC9784628/ /pubmed/36558980 http://dx.doi.org/10.3390/ph15121529 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Marco, Daniel N.
Salas, María Queralt
Gutiérrez-García, Gonzalo
Monge, Inés
Riu, Gisela
Carcelero, Esther
Roma, Joan Ramón
Llobet, Noemí
Arcarons, Jordi
Suárez-Lledó, María
Martínez, Nuria
Pedraza, Alexandra
Domenech, Ariadna
Rosiñol, Laura
Fernández-Avilés, Francesc
Urbano-Ispízua, Álvaro
Rovira, Montserrat
Brunet, Mercè
Martínez, Carmen
Impact of Early Intrapatient Variability of Tacrolimus Concentrations on the Risk of Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide
title Impact of Early Intrapatient Variability of Tacrolimus Concentrations on the Risk of Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide
title_full Impact of Early Intrapatient Variability of Tacrolimus Concentrations on the Risk of Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide
title_fullStr Impact of Early Intrapatient Variability of Tacrolimus Concentrations on the Risk of Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide
title_full_unstemmed Impact of Early Intrapatient Variability of Tacrolimus Concentrations on the Risk of Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide
title_short Impact of Early Intrapatient Variability of Tacrolimus Concentrations on the Risk of Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide
title_sort impact of early intrapatient variability of tacrolimus concentrations on the risk of graft-versus-host disease after allogeneic stem cell transplantation using high-dose post-transplant cyclophosphamide
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9784628/
https://www.ncbi.nlm.nih.gov/pubmed/36558980
http://dx.doi.org/10.3390/ph15121529
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