PMID- 32668748
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 2077-0383 (Print)
IS  - 2077-0383 (Electronic)
IS  - 2077-0383 (Linking)
VI  - 9
IP  - 7
DP  - 2020 Jul 13
TI  - Thiopurines' Metabolites and Drug Toxicity: A Meta-Analysis.
LID - 10.3390/jcm9072216 [doi]
LID - 2216
AB  - 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 x 10(8) RBC) and gastrointestinal 
      intolerance (MD 201.46 pmol/8 x 10(8) RBC), and lower in patients with 
      hepatotoxicity (MD -40.6 pmol x 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 x 
      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 x 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.
FAU - Sousa, Paula
AU  - Sousa P
AD  - Department of Gastroenterology, Viseu Unit, Tondela-Viseu Hospital Centre, 
      3504-509 Viseu, Portugal.
FAU - Estevinho, Maria Manuela
AU  - Estevinho MM
AD  - Department of Biomedicine, Unit of Pharmacology and Therapeutics, University of 
      Porto, 4200-450 Porto, Portugal.
AD  - Department of Gastroenterology, Centro Hospitalar Vila Nova de Gaia/Espinho, 
      4434-502 Vila Nova de Gaia, Portugal.
FAU - Dias, Claudia Camila
AU  - Dias CC
AD  - Department of Community Medicine, Information and Decision in Health, University 
      of Porto, 4200-450 Porto, Portugal.
AD  - Centre for Health Technology and Services Research, University of Porto, 4200-450 
      Porto, Portugal.
FAU - Ministro, Paula
AU  - Ministro P
AD  - Department of Gastroenterology, Viseu Unit, Tondela-Viseu Hospital Centre, 
      3504-509 Viseu, Portugal.
FAU - Kopylov, Uri
AU  - Kopylov U
AD  - Department of Gastroenterology, Sheba Medical Central, Ramat Gan and Sackler 
      Medical School, Tel Aviv University, 52621 Ramat Gan, Israel.
FAU - Danese, Silvio
AU  - Danese S
AD  - Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy.
AD  - Humanitas Clinical and Research Center, IRCCS, 20089 Milan, Italy.
FAU - Peyrin-Biroulet, Laurent
AU  - Peyrin-Biroulet L
AD  - Department of Gastroenterology, Nancy University Hospital, University of 
      Lorraine, 54500 Vandoeuvre-les-Nancy, France.
FAU - Magro, Fernando
AU  - Magro F
AD  - Department of Biomedicine, Unit of Pharmacology and Therapeutics, University of 
      Porto, 4200-450 Porto, Portugal.
AD  - Department of Gastroenterology, Sao Joao University Hospital, 4200-319 Porto, 
      Portugal.
AD  - MedInUP, Centre for Drug Discovery and Innovative Medicines, 4200-319 Porto, 
      Portugal.
LA  - eng
GR  - Investigation Scholarship 2018/Grupo de Estudos de Doenca Inflamatoria 
      Intestinal/
PT  - Journal Article
PT  - Review
DEP - 20200713
PL  - Switzerland
TA  - J Clin Med
JT  - Journal of clinical medicine
JID - 101606588
PMC - PMC7408995
OTO - NOTNLM
OT  - adverse events
OT  - therapeutic drug monitoring
OT  - thiopurines
COIS- P.M. is a consultant for Abbvie, Ferring, Hospira, Janssen, MSD, Pfizer, Takeda. 
      U.K. has received speaker fees from Abbvie, Janssen, Medtronic, and Takeda, 
      research support from Takeda, Medtronic and Janssen, and consulting fees from 
      Takeda, Medtronic and Abbvie. S.D. has served as a speaker, a consultant and an 
      advisory board member for Abbvie, Ferring, Hospira, Johnson & Johnson, Merck, 
      Millennium Takeda, Mundipharma, Pfizer, Tigenix, UCB Pharma and Vifor. L.P.-B. 
      received honoraria from Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, 
      Norgine, Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Biogaran, 
      Boerhinger-Ingelheim, Lilly, HAC-Pharma, Index Pharmaceuticals, Amgen, Sandoz, 
      Forward Pharma GmbH, Celgene, Biogen, Lycera, Samsung Bioepis. F.M. has served as 
      a speaker and received honoraria from Merck Sharp & Dohme, Abbvie, Vifor, Falk, 
      Laboratorios Vitoria, Ferring, Hospira, and Biogen. The other authors have no 
      conflicts of interest to disclose. The funders had no role in the design of the 
      study; in the collection, analyses, or interpretation of data; in the writing of 
      the manuscript, or in the decision to publish the results.
EDAT- 2020/07/17 06:00
MHDA- 2020/07/17 06:01
PMCR- 2020/07/13
CRDT- 2020/07/17 06:00
PHST- 2020/05/24 00:00 [received]
PHST- 2020/07/06 00:00 [revised]
PHST- 2020/07/09 00:00 [accepted]
PHST- 2020/07/17 06:00 [entrez]
PHST- 2020/07/17 06:00 [pubmed]
PHST- 2020/07/17 06:01 [medline]
PHST- 2020/07/13 00:00 [pmc-release]
AID - jcm9072216 [pii]
AID - jcm-09-02216 [pii]
AID - 10.3390/jcm9072216 [doi]
PST - epublish
SO  - J Clin Med. 2020 Jul 13;9(7):2216. doi: 10.3390/jcm9072216.