title: Therapeutic drug monitoring of thiopurine metabolites in adult thiopurine tolerant IBD patients on maintenance therapy.
abstract: OBJECTIVE
  Therapeutic drug monitoring of active metabolites of thiopurines, azathioprine and 6-mercaptopurine, is relatively new. The proposed therapeutic threshold level of the active 6-thioguanine nucleotides (6-TGN) is ≥235 pmol/8×10(8) erythrocytes. The aim of this prospective cross-sectional study was to compare 6-TGN levels in adult thiopurine tolerant IBD patients with an exacerbation with those in remission, and to determine the therapeutic 6-TGN cut-off level.
  
  
  METHODS
  Hundred IBD patients were included. Outcome measures were thiopurine metabolite levels, calculated therapeutic 6-TGN cut-off level, CDAI/CAI scores, thiopurine dose and TPMT enzyme activity.
  
  
  RESULTS
  Forty-one patients had an exacerbation, 59 patients were in remission. In 17% of all patients 6-TGN levels were compatible with non-compliance. The median 6-TGN levels were not significantly different between the exacerbation and remission group (227 versus 263 pmol/8×10(8) erythrocytes, p=0.29). The previous reported therapeutic 6-TGN cut-off level of 235 pmol/8×10(8) erythrocytes was confirmed in this study. Twenty-six of the 41 patients (63%) with active disease had 6-TGN levels below this threshold and 24 of 59 IBD patients (41%) in clinical remission (p=0.04).
  
  
  CONCLUSIONS
  Thiopurine non-compliance occurs frequently both in active and quiescent disease. 6-TGN levels below or above the therapeutic threshold are associated with a significant higher chance of IBD exacerbation and remission, respectively. These data support the role of therapeutic drug monitoring in thiopurine maintenance therapy in IBD to reveal non-compliance or underdosing, and can be used as a practical tool to optimize thiopurine therapy, especially in case of thiopurine non-response.
authors.affiliation: Department of Gastroenterology and Hepatology, Catharina Hospital, Eindhoven, The Netherlands. lennard.gilissen@cze.nl
authors.forename: Lennard P L
authors.initials: LP
authors.lastname: Gilissen
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Wong
authors.forename: Leopold G J B
authors.initials: LG
authors.lastname: Engels
authors.forename: Jörgen
authors.initials: J
authors.lastname: Bierau
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Bakker
authors.forename: Aimée D C
authors.initials: AD
authors.lastname: Paulussen
authors.forename: Mariëlle J
authors.initials: MJ
authors.lastname: Romberg-Camps
authors.forename: Arnold
authors.initials: A
authors.lastname: Stronkhorst
authors.forename: Paul
authors.initials: P
authors.lastname: Bus
authors.forename: Laurens P
authors.initials: LP
authors.lastname: Bos
authors.forename: Piet M
authors.initials: PM
authors.lastname: Hooymans
authors.forename: Reinhold W
authors.initials: RW
authors.lastname: Stockbrügger
authors.forename: Cees
authors.initials: C
authors.lastname: Neef
authors.forename: Ad A M
authors.initials: AA
authors.lastname: Masclee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000378:metabolism / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D003430:Cross-Sectional Studies; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D005819:Genetic Markers; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D060046:Maintenance Chemotherapy; D008297:Male; D015122:Mercaptopurine / Q000378:metabolism / Q000627:therapeutic use*; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D011446:Prospective Studies; D012720:Severity of Illness Index; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000097:blood; D013873:Thionucleotides / Q000097:blood*; D055815:Young Adult
chemical_list: D054316:Biomarkers, Pharmacological; D005819:Genetic Markers; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; D013868:Thioinosine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine