Cargando…

Thiopurines’ Metabolites and Drug Toxicity: A Meta-Analysis

Many questions remain unanswered regarding therapeutic drug monitoring (TDM) utility with thiopurines. This study aims to establish a relationship between thiopurines’ metabolites and drug toxicity. We performed a systematic review with inclusion of studies evaluating the relationship between thiopu...

Descripción completa

Detalles Bibliográficos
Autores principales: Sousa, Paula, Estevinho, Maria Manuela, Dias, Cláudia Camila, Ministro, Paula, Kopylov, Uri, Danese, Silvio, Peyrin-Biroulet, Laurent, Magro, Fernando
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408995/
https://www.ncbi.nlm.nih.gov/pubmed/32668748
http://dx.doi.org/10.3390/jcm9072216
_version_ 1783567961521389568
author Sousa, Paula
Estevinho, Maria Manuela
Dias, Cláudia Camila
Ministro, Paula
Kopylov, Uri
Danese, Silvio
Peyrin-Biroulet, Laurent
Magro, Fernando
author_facet Sousa, Paula
Estevinho, Maria Manuela
Dias, Cláudia Camila
Ministro, Paula
Kopylov, Uri
Danese, Silvio
Peyrin-Biroulet, Laurent
Magro, Fernando
author_sort Sousa, Paula
collection PubMed
description Many questions remain unanswered regarding therapeutic drug monitoring (TDM) utility with thiopurines. This study aims to establish a relationship between thiopurines’ metabolites and drug toxicity. We performed a systematic review with inclusion of studies evaluating the relationship between thiopurines’ metabolites and drug toxicity. Meta-analysis of mean difference (MD), correlations and odds ratio (OR) was performed. We identified 21,240 records, 72 of which were eligible for meta-analysis. Levels of 6-thioguanine nucleotides (6-TGN) were higher in patients with leukopenia (MD 127.06 pmol/8 × 10(8) RBC) and gastrointestinal intolerance (MD 201.46 pmol/8 × 10(8) RBC), and lower in patients with hepatotoxicity (MD −40.6 pmol × 10(8) RBC). We established a significant correlation between 6-TGN and leukocytes (r = −0.21), neutrophils (r = −0.24) and alanine aminotransferase levels (r = −0.24). OR for leukopenia in patients with elevated 6-TGN was 4.63 (95% CI 2.24; 9.57). An optimal cut-off of 135 pmol/8 × 10(8) RBC for leukopenia was calculated (sensitivity 75.4%; specificity 46.4%). 6-methylmercaptopurine ribonucleotides (6-MMPR) were significantly associated with hepatotoxicity (MD 3241.2 pmol/8 × 10(8) RBC; OR 4.28; 95% CI 3.20; 5.71). Levels of 6-MMPR measured in the first 8 weeks of treatment were associated with leukopenia. We conclude that TDM could be used to prevent thiopurines’ toxicity. As optimal metabolites level may vary according to indication, physicians may adapt posology to decrease toxicity without compromising efficacy.
format Online
Article
Text
id pubmed-7408995
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-74089952020-08-26 Thiopurines’ Metabolites and Drug Toxicity: A Meta-Analysis Sousa, Paula Estevinho, Maria Manuela Dias, Cláudia Camila Ministro, Paula Kopylov, Uri Danese, Silvio Peyrin-Biroulet, Laurent Magro, Fernando J Clin Med Review Many questions remain unanswered regarding therapeutic drug monitoring (TDM) utility with thiopurines. This study aims to establish a relationship between thiopurines’ metabolites and drug toxicity. We performed a systematic review with inclusion of studies evaluating the relationship between thiopurines’ metabolites and drug toxicity. Meta-analysis of mean difference (MD), correlations and odds ratio (OR) was performed. We identified 21,240 records, 72 of which were eligible for meta-analysis. Levels of 6-thioguanine nucleotides (6-TGN) were higher in patients with leukopenia (MD 127.06 pmol/8 × 10(8) RBC) and gastrointestinal intolerance (MD 201.46 pmol/8 × 10(8) RBC), and lower in patients with hepatotoxicity (MD −40.6 pmol × 10(8) RBC). We established a significant correlation between 6-TGN and leukocytes (r = −0.21), neutrophils (r = −0.24) and alanine aminotransferase levels (r = −0.24). OR for leukopenia in patients with elevated 6-TGN was 4.63 (95% CI 2.24; 9.57). An optimal cut-off of 135 pmol/8 × 10(8) RBC for leukopenia was calculated (sensitivity 75.4%; specificity 46.4%). 6-methylmercaptopurine ribonucleotides (6-MMPR) were significantly associated with hepatotoxicity (MD 3241.2 pmol/8 × 10(8) RBC; OR 4.28; 95% CI 3.20; 5.71). Levels of 6-MMPR measured in the first 8 weeks of treatment were associated with leukopenia. We conclude that TDM could be used to prevent thiopurines’ toxicity. As optimal metabolites level may vary according to indication, physicians may adapt posology to decrease toxicity without compromising efficacy. MDPI 2020-07-13 /pmc/articles/PMC7408995/ /pubmed/32668748 http://dx.doi.org/10.3390/jcm9072216 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Sousa, Paula
Estevinho, Maria Manuela
Dias, Cláudia Camila
Ministro, Paula
Kopylov, Uri
Danese, Silvio
Peyrin-Biroulet, Laurent
Magro, Fernando
Thiopurines’ Metabolites and Drug Toxicity: A Meta-Analysis
title Thiopurines’ Metabolites and Drug Toxicity: A Meta-Analysis
title_full Thiopurines’ Metabolites and Drug Toxicity: A Meta-Analysis
title_fullStr Thiopurines’ Metabolites and Drug Toxicity: A Meta-Analysis
title_full_unstemmed Thiopurines’ Metabolites and Drug Toxicity: A Meta-Analysis
title_short Thiopurines’ Metabolites and Drug Toxicity: A Meta-Analysis
title_sort thiopurines’ metabolites and drug toxicity: a meta-analysis
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408995/
https://www.ncbi.nlm.nih.gov/pubmed/32668748
http://dx.doi.org/10.3390/jcm9072216
work_keys_str_mv AT sousapaula thiopurinesmetabolitesanddrugtoxicityametaanalysis
AT estevinhomariamanuela thiopurinesmetabolitesanddrugtoxicityametaanalysis
AT diasclaudiacamila thiopurinesmetabolitesanddrugtoxicityametaanalysis
AT ministropaula thiopurinesmetabolitesanddrugtoxicityametaanalysis
AT kopylovuri thiopurinesmetabolitesanddrugtoxicityametaanalysis
AT danesesilvio thiopurinesmetabolitesanddrugtoxicityametaanalysis
AT peyrinbirouletlaurent thiopurinesmetabolitesanddrugtoxicityametaanalysis
AT magrofernando thiopurinesmetabolitesanddrugtoxicityametaanalysis