title: Prospective Evaluation of Pharmacogenomics and Metabolite Measurements upon Azathioprine Therapy in Inflammatory Bowel Disease: An Observational Study.
abstract: Up to approximately 40% to 50% of patients discontinue thiopurine therapy during the course of inflammatory bowel disease (IBD). We investigated the role of the metabolite thiopurine in IBD treatment. This was a prospective study. IBD patients receiving azathioprine (AZA) were prospectively included. Thiopurine methyltransferase (TPMT) genotypes were examined before therapy, and thiopurine metabolite levels were examined at weeks 2, 4, 8, 12, 24, and 48. In total, 132 patients were included. The frequency of leucopenia increased at 6-thioguanine nucleotide (6-TGN) levels ≥420  pmol/8 × 10(8) RBC (odds ratio [OR] = 7.9; 95% confidence interval (95%CI): 3.5-18.0; P < 0.001) and increased more during the initial 12 weeks of thiopurine therapy (OR = 16.0; 95%CI: 5.7-44.9; P < 0.001). The patients with 6-TGN levels ≥420 pmol/8 × 10 RBC at weeks 4, 8, and 12 had an increased likelihood of leucopenia. Clinical response increased at 6-TGN levels ≥225 pmol/8 × 10(8) RBC (OR = 13.5; 95% CI: 3.7-48.9; P < 0.001) in Crohn disease (CD) patients. The CD patients with 6-TGN levels ≥225 pmol/8 × 10(8) RBC at weeks 8, 12, and 24 had an increased likelihood of successful clinical response. TPMT*3C had a specificity of 100%, but a sensitivity of 8% for predicting leucopenia.A 6-TGN level between 225 and 420 pmol/8 × 10(8) RBC could be a therapeutic window in patients receiving AZA therapy, and it could likely predict leucopenia in the initial 12 weeks of AZA therapy and a reasonable chance of successful clinical response in CD patients. The value of TPMT genotyping before thiopurine therapy is limited in Chinese patients with IBD, considering the low sensitivity of predicting leucopenia.
authors.affiliation: From the Department of Gastroenterology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou (ZF, CP, CY, XF); Department of Gastroenterology, the First Affiliated Hospital, Sun Yat-sen University (ZF, GX, CB, XY, CM, HP); Department of Gastroenterology, the Sixth Affiliated Hospital of Sun Yat-sen University (GX, HP); Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University (DL, LH, WX, BH, ZL, HM); and Department of Pharmacology, the First Affiliated Hospital of Jinan University (LH), Guangzhou, China).
authors.forename: Zhang
authors.initials: Z
authors.lastname: Fangbin
authors.forename: Gao
authors.initials: G
authors.lastname: Xiang
authors.forename: Ding
authors.initials: D
authors.lastname: Liang
authors.forename: Liu
authors.initials: L
authors.lastname: Hui
authors.forename: Wang
authors.initials: W
authors.lastname: Xueding
authors.forename: Chen
authors.initials: C
authors.lastname: Baili
authors.forename: Bi
authors.initials: B
authors.lastname: Huichang
authors.forename: Xiao
authors.initials: X
authors.lastname: Yinglian
authors.forename: Cheng
authors.initials: C
authors.lastname: Peng
authors.forename: Zhao
authors.initials: Z
authors.lastname: Lizi
authors.forename: Chu
authors.initials: C
authors.lastname: Yanjun
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
authors.forename: Chen
authors.initials: C
authors.lastname: Minhu
authors.forename: Huang
authors.initials: H
authors.lastname: Min
authors.forename: Hu
authors.initials: H
authors.lastname: Pinjin
mesh_terms: D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000493:pharmacokinetics / Q000627:therapeutic use; D002681:China; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005820:Genetic Testing; D006150:Guanine Nucleotides / Q000032:analysis; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007970:Leukopenia / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010597:Pharmacogenetics; D011237:Predictive Value of Tests; D011446:Prospective Studies; D013873:Thionucleotides / Q000032:analysis
chemical_list: D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine