title: Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease.
abstract: OBJECTIVE
  Only a quarter of thiopurine-induced myelotoxicity in inflammatory bowel disease [IBD] patients is related to thiopurine S-methyltransferase deficiency. We determined the predictive value of 6-thioguanine nucleotide [6-TGN] and 6-methylmercaptopurine ribonucleotide [6-MMPR] concentrations 1 week after initiation [T1] for development of leukopenia during the first 8 weeks of thiopurine treatment.
  
  
  METHODS
  The study was performed in IBD patients starting thiopurine therapy as part of the Dutch randomized controlled TOPIC trial [ClinicalTrials.gov NCT00521950]. Blood samples for metabolite measurement were collected at T1. Leukopenia was defined by leukocyte counts of <3.0 × 109/L. For comparison, patients without leukopenia who completed the 8 weeks on the stable dose were selected from the first 272 patients of the TOPIC trial.
  
  
  RESULTS
  Thirty-two patients with, and 162 patients without leukopenia were analysed. T1 threshold 6-TGN concentrations of 213 pmol/8 × 108erythrocytes and 3525 pmol/8 × 108erythrocytes for 6-MMPR were defined: patients exceeding these values were at increased leukopenia risk (odds ratio [OR] 6.2 [95% CI: 2.8-13.8] and 5.9 [95% CI: 2.7-13.3], respectively). Leukopenia rates were higher in patients treated with mercaptopurine, compared with azathioprine (OR 7.3 [95% CI: 3.1-17.0]), and concurrent anti-TNF therapy (OR 5.1 [95% CI: 1.6-16.4]). Logistic regression analysis of thiopurine type, threshold concentrations, and concurrent anti-tumour necrosis factor [TNF] therapy revealed that elevations of both T1 6-TGN and 6-MMPR resulted in the highest risk for leukopenia, followed by exceeding only the T1 6-MMPR or 6-TGN threshold concentration (area under the curve 0.84 [95% CI: 0.76-0.92]).
  
  
  CONCLUSIONS
  In ~80% of patients, leukopenia could be explained by T1 6-TGN and/or 6-MMPR elevations. Validation of the predictive model is needed before implementing in clinical practice.
authors.affiliation: Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands d.wong@zuyderland.nl.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Wong
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Sita H
authors.initials: SH
authors.lastname: Vermeulen
authors.affiliation: Department of Clinical Pharmacy, Máxima Medical Centre, Veldhoven, The Netherlands.
authors.forename: Luc J J
authors.initials: LJ
authors.lastname: Derijks
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Corine J
authors.initials: CJ
authors.lastname: van Marrewijk
authors.affiliation: Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, The Netherlands.
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Scheffer
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Gastroenterology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: de Jong
authors.affiliation: Department of Gastroenterology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands.
authors.forename: Leopold G J B
authors.initials: LG
authors.lastname: Engels
authors.affiliation: Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: André L M
authors.initials: AL
authors.lastname: Verbeek
authors.affiliation: Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands.
authors.forename: Piet M
authors.initials: PM
authors.lastname: Hooymans
mesh_terms: D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004342:Drug Hypersensitivity / Q000175:diagnosis; D004347:Drug Interactions; D005260:Female; D006150:Guanine Nucleotides / Q000032:analysis*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000378:metabolism; D007958:Leukocyte Count / Q000379:methods; D007970:Leukopenia / Q000139:chemically induced / Q000175:diagnosis / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D009426:Netherlands; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000175:diagnosis; D015203:Reproducibility of Results; D018570:Risk Assessment / Q000379:methods; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000032:analysis; D013873:Thionucleotides / Q000032:analysis*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; D014409:Tumor Necrosis Factor-alpha; C003964:6-thioguanylic acid; D013868:Thioinosine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D015122:Mercaptopurine; D001379:Azathioprine
keywords: Thiopurines; inflammatory bowel disease; toxicity