Novel assay to improve therapeutic drug monitoring of thiopurines in inflammatory bowel disease

• Published in: Journal of Crohn's and colitis Vol. 8; no. 12; pp. 1702 - 1709
• Main Authors: Vikingsson, Svante, Andersson, David, Almer, Sven, Peterson, Curt, Hindorf, Ulf
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 01.12.2014
• Subjects: Adolescent; Adult; Aged; Azathioprine; Azathioprine - blood; Azathioprine - therapeutic use; Clinical Medicine; Cross-Sectional Studies; Drug Monitoring - methods; Erythrocytes - chemistry; Female; Gastroenterologi; Gastroenterology and Hepatology; GTP Phosphohydrolases - blood; Guanine Nucleotides - blood; HPLC; Humans; Immunosuppressive Agents - blood; Immunosuppressive Agents - therapeutic use; Individualized medicine; Inflammatory bowel diseases; Inflammatory Bowel Diseases - drug therapy; Klinisk medicin; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Mercaptopurine - blood; Mercaptopurine - therapeutic use; Methylthioinosine - blood; Middle Aged; Purines; Thioguanine - blood; Thioinosine - analogs & derivatives; Thioinosine - blood; Thionucleotides - blood; Thiopurine; Young Adult; Purines; Inflammatory bowel diseases; Individualized medicine; Azathioprine; HPLC; Thiopurine
• ISSN: 1873-9946; 1876-4479; 1876-4479
• DOI: 10.1016/j.crohns.2014.08.009

The thiopurines are widely used in the treatment of inflammatory bowel disease, but are limited by poor dose–effect relationship. The objective was to assess the ability of a novel assay, determining the mono-, di-, and triphosphates, of thioguanine as well as methylthioinosine as individual metabolites in erythrocytes, to predict clinical outcome compared to a routine assay, determining metabolites as sums. Samples from 79 patients with Crohn's disease or ulcerative colitis treated with azathioprine or mercaptopurine were analysed by both assays. Clinical status was determined by the Harvey–Bradshaw and Walmsley indices. The genotypes of thiopurine methyltransferase (TPMT) and inosine triphosphatase were determined. TPMT wild-type patients with thioguanine nucleotide (TGN) levels below the cut-off level were more likely to have active disease when TGN was measured by the novel assay (p=0.02), and when thioguanosine triphosphate (TGTP) was measured separately (p=0.01). When TGN was measured by the routine assay the correlation was not evident (p=0.12). Neither TGN levels nor TGTP correlated to disease activity in TPMT deficient patients. Patients with methyl thioinosine nucleotide (meTIN) levels above 1500pmol/8×10^8 RBCs were more likely to have active disease (p=0.07). We observed good correlations between the mono-, di-, and triphosphates and their respective sums (R2>0.88). The novel TGN assay was better in predicting clinical outcome compared to the routine assay, while determination of TGTP had no clinical advantage and TGTP ratio was not correlated to disease activity.