Thiopurines' Metabolites and Drug Toxicity: A Meta-Analysis.
Fiche publication
Date publication
juillet 2020
Journal
Journal of clinical medicine
Auteurs
Membres identifiés du Cancéropôle Est :
Pr PEYRIN-BIROULET Laurent
Tous les auteurs :
Sousa P, Estevinho MM, Dias CC, Ministro P, Kopylov U, Danese S, Peyrin-Biroulet L, Magro F
Lien Pubmed
Résumé
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 RBC) and gastrointestinal intolerance (MD 201.46 pmol/8 × 10 RBC), and lower in patients with hepatotoxicity (MD -40.6 pmol × 10 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 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 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.
Mots clés
adverse events, therapeutic drug monitoring, thiopurines
Référence
J Clin Med. 2020 Jul 13;9(7):