title: Relationship between azathioprine dosage and thiopurine metabolites in pediatric IBD patients: identification of covariables using multilevel analysis.
abstract: BACKGROUND
  Previous studies have reported no or only a very poor correlation between 6-methylmercaptopurine/6-thioguanine nucleotide (6-MeMPN/6-TGN) and azathioprine (AZA) dose in the treatment of inflammatory bowel disease (IBD). However, metabolite levels are often repeatedly measured yielding a hierarchical data structure that requires more appropriate data analysis.
  
  
  METHODS
  This study explored the relationship between the weight-based dosage of AZA and metabolites levels in 86 pediatric IBD patients using multilevel analysis. Other covariates related to patient characteristics and treatment were evaluated.
  
  
  RESULTS
  This is the first study to demonstrate positive correlations between AZA dose and 6-TGN and 6-MeMPN levels and 6-MeMPN/6-TGN ratio (P < 0.001) in IBD children. Other novel predictors of metabolites were reported. Younger children exhibited lower 6-TGN and 6-MeMPN levels, probably suggesting age-related differences in metabolism and/or absorption of thiopurines. Coadministration of infliximab resulted in a significant increase in 6-TGN levels (P = 0.023). Moreover, alanine aminotransferase values positively correlated with 6-MeMPN levels (P = 0.032). The duration of AZA therapy, gender, and thiopurine methyltransferase activity were associated with metabolite levels. The wide interindividual variability in metabolite levels that accounted for 67.7%, 48.6%, and 49.4% of variance in the 6-TGN and 6-MeMPN levels and the ratio, respectively, were confirmed.
  
  
  CONCLUSIONS
  The reliable AZA dose-metabolites relationship is useful for clinicians to guide the dosing regimen to maximize clinical response and minimize side effects or to consider alternative therapies when patients have preferential production of the toxic 6-MeMPN. These results may be of potential interest for optimizing thiopurine therapy to achieve safe and efficacious AZA use in pediatric IBD patients.
authors.affiliation: Pharmacie Clinique, Pharmacocinétique et Évaluation du Médicament, Université de Lyon, Université Lyon 1, Lyon, France.
authors.forename: Thi-Van-Anh
authors.initials: TV
authors.lastname: Nguyen
authors.forename: Dinh H
authors.initials: DH
authors.lastname: Vu
authors.forename: Thi-Mai-Hoang
authors.initials: TM
authors.lastname: Nguyen
authors.forename: Alain
authors.initials: A
authors.lastname: Lachaux
authors.forename: Roselyne
authors.initials: R
authors.lastname: Boulieu
mesh_terms: D000293:Adolescent; D000367:Age Factors; D001379:Azathioprine / Q000008:administration & dosage*; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D006150:Guanine Nucleotides / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000378:metabolism; D055361:Multilevel Analysis / Q000379:methods*; D012189:Retrospective Studies; D013873:Thionucleotides / Q000378:metabolism*
chemical_list: D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; C010240:6-methylthiopurine; D015122:Mercaptopurine; D001379:Azathioprine