@article {10504, title = {Multicentric Case-Control Study on Azathioprine Dose and Pharmacokinetics in Early-onset Pediatric Inflammatory Bowel Disease.}, journal = {Inflamm Bowel Dis}, volume = {23}, year = {2017}, month = {2017 04}, pages = {628-634}, abstract = {

BACKGROUND: 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{\textquoteright} age in children with IBD treated at 6 tertiary pediatric referral centers.

METHODS: 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.

RESULTS: 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{\textperiodcentered}kg{\textperiodcentered}d, P value = 1.1 {\texttimes} 10). Different doses resulted in comparable azathioprine active thioguanine nucleotide metabolite concentrations (median 263 versus 366 pmol/8 {\texttimes} 10 erythrocytes, P value = 0.41) and methylmercaptopurine nucleotide concentrations (median 1455 versus 1532 pmol/8 {\texttimes} 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 {\texttimes} 10 erythrocytes{\textperiodcentered}mg{\textperiodcentered}kg{\textperiodcentered}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).

CONCLUSIONS: This study demonstrated that patients with early-onset IBD present increased inactivating azathioprine metabolism, likely because of elevated activity of the enzyme thiopurine methyltransferase.

}, keywords = {Adolescent, Age of Onset, Antimetabolites, Azathioprine, Case-Control Studies, Child, Child, Preschool, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Erythrocytes, Female, Guanine Nucleotides, Humans, Inflammatory Bowel Diseases, Male, Mercaptopurine, Methyltransferases, Thioguanine}, issn = {1536-4844}, doi = {10.1097/MIB.0000000000001051}, author = {Stocco, Gabriele and Martelossi, Stefano and Arrigo, Serena and Barabino, Arrigo and Aloi, Marina and Martinelli, Massimo and Miele, Erasmo and Knafelz, Daniela and Romano, Claudio and Naviglio, Samuele and Favretto, Diego and Cuzzoni, Eva and Franca, Raffaella and Decorti, Giuliana and Ventura, Alessandro} }