title: Multicentric Case-Control Study on Azathioprine Dose and Pharmacokinetics in Early-onset Pediatric Inflammatory Bowel Disease.
abstract: Early-onset inflammatory bowel disease (IBD) is generally aggressive, with a high probability of complications and need of surgery. Despite the introduction of highly effective biological drugs, treatment with azathioprine continues to be important even for early-onset IBD; however, in these patients azathioprine response seems to be reduced. This study evaluated azathioprine doses, metabolite concentrations, and their associations with patients' age in children with IBD treated at 6 tertiary pediatric referral centers.
  
  
  
  Azathioprine doses, metabolites, and clinical effects were assessed after at least 3 months of therapy in 17 early-onset (age < 6 yr, cases) and 51 nonearly-onset (aged > 12 and <18 yrs, controls) patients with IBD. Azathioprine dose was titrated on therapeutic efficacy (response and adverse effects). Azathioprine metabolites and thiopurine methyltransferase activity were determined by high-performance liquid chromatography with ultra violet-vis detection (HPLC-UV) methods.
  
  
  
  Frequency of patients in remission was similar among early-onset and control groups, respectively (82% and 84%, P value = 0.72). Early-onset patients required higher doses of azathioprine (median 2.7 versus 2.0 mg·kg·d, P value = 1.1 × 10). Different doses resulted in comparable azathioprine active thioguanine nucleotide metabolite concentrations (median 263 versus 366 pmol/8 × 10 erythrocytes, P value = 0.41) and methylmercaptopurine nucleotide concentrations (median 1455 versus 1532 pmol/8 × 10 erythrocytes, P value = 0.60). Lower ratios between thioguanine nucleotide metabolites and azathioprine doses were found in early-onset patients (median 98 versus 184 pmol/8 × 10 erythrocytes·mg·kg·d, P value = 0.017). Interestingly, early-onset patients presented also higher thiopurine methyltransferase activity (median 476 versus 350 nmol methylmercaptopurine/mg hemoglobin/h, P-value = 0.046).
  
  
  
  This study demonstrated that patients with early-onset IBD present increased inactivating azathioprine metabolism, likely because of elevated activity of the enzyme thiopurine methyltransferase.
authors.affiliation: *Department of Life Sciences, University of Trieste, Trieste, Italy; †Department of Pediatrics, Institute for Maternal and Child Health Burlo Garofolo, Trieste, Italy; ‡Gastroenterology and Endoscopy Unit, Gaslini Institute for Children, Genoa, Italy; §Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy; ‖Department of Translational Medical Science, Section of Pediatrics, University of Naples Federico II, Naples, Italy; ¶Hepatology, Gastroenterology and Nutrition Unit, Bambino Gesù Children's Hospital, Rome, Italy; **Department of Pediatric, University of Messina, Messina, Italy; ††PhD School in Science of Reproduction and Development, University of Trieste, Trieste, Italy; and ‡‡Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Stocco
authors.forename: Stefano
authors.initials: S
authors.lastname: Martelossi
authors.forename: Serena
authors.initials: S
authors.lastname: Arrigo
authors.forename: Arrigo
authors.initials: A
authors.lastname: Barabino
authors.forename: Marina
authors.initials: M
authors.lastname: Aloi
authors.forename: Massimo
authors.initials: M
authors.lastname: Martinelli
authors.forename: Erasmo
authors.initials: E
authors.lastname: Miele
authors.forename: Daniela
authors.initials: D
authors.lastname: Knafelz
authors.forename: Claudio
authors.initials: C
authors.lastname: Romano
authors.forename: Samuele
authors.initials: S
authors.lastname: Naviglio
authors.forename: Diego
authors.initials: D
authors.lastname: Favretto
authors.forename: Eva
authors.initials: E
authors.lastname: Cuzzoni
authors.forename: Raffaella
authors.initials: R
authors.lastname: Franca
authors.forename: Giuliana
authors.initials: G
authors.lastname: Decorti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ventura
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000963:Antimetabolites / Q000493:pharmacokinetics*; D001379:Azathioprine / Q000493:pharmacokinetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy*; D008297:Male; D015122:Mercaptopurine / Q000031:analogs & derivatives / Q000097:blood; D008780:Methyltransferases / Q000097:blood; D013866:Thioguanine / Q000097:blood
chemical_list: D000963:Antimetabolites; D006150:Guanine Nucleotides; C010240:6-methylthiopurine; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine; D001379:Azathioprine