PMID- 33532972 OWN - NLM STAT- MEDLINE DCOM- 20220216 LR - 20220531 IS - 1573-2568 (Electronic) IS - 0163-2116 (Print) IS - 0163-2116 (Linking) VI - 67 IP - 1 DP - 2022 Jan TI - Adverse Events of Thiopurine Therapy in Pediatric Inflammatory Bowel Disease and Correlations with Metabolites: A Cohort Study. PG - 241-251 LID - 10.1007/s10620-021-06836-3 [doi] AB - BACKGROUND: In the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity. AIMS: We assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival. METHODS: We performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan-Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman's correlation coefficient. RESULTS: Of 391 patients with IBD, 233 patients (162 Crohn's disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase. CONCLUSIONS: Approximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities. CI - (c) 2021. The Author(s). FAU - Jagt, Jasmijn Z AU - Jagt JZ AD - Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1105 AZ, Amsterdam, The Netherlands. j.jagt1@amsterdamumc.nl. FAU - Pothof, Christine D AU - Pothof CD AD - Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1105 AZ, Amsterdam, The Netherlands. FAU - Buiter, Hans J C AU - Buiter HJC AD - Department of Clinical Pharmacology and Pharmacy, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1105 AZ, Amsterdam, The Netherlands. FAU - van Limbergen, Johan E AU - van Limbergen JE AD - Department of Pediatric Gastroenterology, UMC, Emma Children's Hospital, Amsterdam, Academic Medical Centre, 1081 HV, Amsterdam, The Netherlands. FAU - van Wijk, Michiel P AU - van Wijk MP AD - Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1105 AZ, Amsterdam, The Netherlands. AD - Department of Pediatric Gastroenterology, UMC, Emma Children's Hospital, Amsterdam, Academic Medical Centre, 1081 HV, Amsterdam, The Netherlands. FAU - Benninga, Marc A AU - Benninga MA AD - Department of Pediatric Gastroenterology, UMC, Emma Children's Hospital, Amsterdam, Academic Medical Centre, 1081 HV, Amsterdam, The Netherlands. FAU - de Boer, Nanne K H AU - de Boer NKH AD - Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism Research Institute, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1081 HV, Amsterdam, The Netherlands. FAU - de Meij, Tim G J AU - de Meij TGJ AD - Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1105 AZ, Amsterdam, The Netherlands. AD - Department of Pediatric Gastroenterology, UMC, Emma Children's Hospital, Amsterdam, Academic Medical Centre, 1081 HV, Amsterdam, The Netherlands. LA - eng PT - Journal Article DEP - 20210203 PL - United States TA - Dig Dis Sci JT - Digestive diseases and sciences JID - 7902782 RN - 0 (Antimetabolites) RN - 0 (Biomarkers, Pharmacological) RN - 0 (Guanine Nucleotides) RN - 0 (Thionucleotides) RN - 15867-02-4 (6-thioguanylic acid) RN - 6V404DV25O (6-methylthiopurine) RN - E7WED276I5 (Mercaptopurine) RN - MRK240IY2L (Azathioprine) SB - IM MH - Adolescent MH - Antimetabolites/administration & dosage/adverse effects/pharmacokinetics MH - *Azathioprine/administration & dosage/adverse effects/pharmacokinetics MH - Biomarkers, Pharmacological/blood MH - Child MH - Cohort Studies MH - *Colitis, Ulcerative/drug therapy/epidemiology/metabolism/pathology MH - *Crohn Disease/drug therapy/epidemiology/metabolism/pathology MH - Drug Substitution/methods/statistics & numerical data MH - *Drug-Related Side Effects and Adverse Reactions/blood/diagnosis/epidemiology/etiology MH - Female MH - Guanine Nucleotides/blood MH - Humans MH - Male MH - Mercaptopurine/administration & dosage/adverse effects/*analogs & derivatives/pharmacokinetics MH - Netherlands/epidemiology MH - Retrospective Studies MH - Thionucleotides/blood MH - Withholding Treatment/*statistics & numerical data PMC - PMC8741678 OTO - NOTNLM OT - Adverse events OT - Inflammatory bowel disease OT - Metabolites OT - Pediatrics OT - Thiopurines COIS- NdB has served as a speaker for AbbVie and MSD and has served as consultant and principal investigator for TEVA Pharma BV and Takeda. He has received a (unrestricted) research grant from Dr. Falk, TEVA Pharma BV, MLDS and Takeda. JvL reports consulting, travel and/or speaker fees and research support from AbbVie, Janssen, Nestle Health Science, Novalac, Pfizer, Merck, P&G, GSK, Illumina, Otsuka. JJ, CP, HB, MvW, MB, and TdM have nothing to declare. EDAT- 2021/02/04 06:00 MHDA- 2022/02/17 06:00 PMCR- 2021/02/03 CRDT- 2021/02/03 06:03 PHST- 2020/11/06 00:00 [received] PHST- 2021/01/07 00:00 [accepted] PHST- 2021/02/04 06:00 [pubmed] PHST- 2022/02/17 06:00 [medline] PHST- 2021/02/03 06:03 [entrez] PHST- 2021/02/03 00:00 [pmc-release] AID - 10.1007/s10620-021-06836-3 [pii] AID - 6836 [pii] AID - 10.1007/s10620-021-06836-3 [doi] PST - ppublish SO - Dig Dis Sci. 2022 Jan;67(1):241-251. doi: 10.1007/s10620-021-06836-3. Epub 2021 Feb 3.