Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease

Ansari, Azhar; Arenas, Monica; Greenfield, S.; Morris, Danielle; Lindsay, James O.; Gilshenan, Kristen; Smith, Melissa A.; Lewis, Cathryn M.; Marinaki, Anthony M.; Duley, John A.; Sanderson, Jeremy

doi:10.1111/j.1365-2036.2008.03788.x

Cited by 153 publications

(141 citation statements)

References 56 publications

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“…On the contrary, several studies in Western samples have addressed the impact of TPMT activity and genotype on the clinical response of IBD patients treated with AZA/6-MP and suggested that measurement of TPMT activity might predict clinical response to AZA/6-MP. 15,16 At present, the reasons for discrepancies among these studies are unclear. However, one possible explanation for these discrepancies is that the Asian population has genetic backgrounds of TPMT that are different from those of the Caucasian population.…”

Section: Discussionmentioning

confidence: 99%

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

et al. 2009

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There is a lack of research describing the associations between thiopurine methyltransferase (TPMT)/inosine triphosphate pyrophosphatase (ITPA) genotypes and long-term clinical outcomes. We investigated whether TPMT/ITPA genotypes predicted long-term clinical response in Korean patients with inflammatory bowel diseases (IBDs) undergoing thiopurine treatment. A total of 204 patients with IBD in whom thiopurine treatment was indicated were enrolled and categorized by TPMT and ITPA genotypes. Long-term follow-up clinical data for these patients were analyzed with specific focus on disease relapse. Of the 204 patients, 162 (79.4%) patients using thiopurines achieved remission and were included in an analysis of long-term clinical outcomes. There were no significant differences in disease relapse-free survival between wild and mutant types of TPMT (P¼0.903) or ITPA (P¼0.392), according to the results of the log-rank analysis. Our study suggests that TPMT and ITPA genotypes may not affect the rates of disease relapse in IBD patients treated with thiopurines. Further studies are indicated to confirm the utility of TPMT/ITPA genotyping to guide clinicians formulating individualized treatments for IBD patients requiring thiopurine therapy. Keywords: azathioprine; inflammatory bowel disease; inosine triphosphate pyrophosphatase; relapse; thiopurine S-methyl transferase INTRODUCTION Thiopurine drugs, 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA), are effective for the induction and maintenance of remission in patients with inflammatory bowel disease (IBD). 1,2 There has been tremendous interest with regard to thiopurine metabolism as a means of identifying ways in which individual therapy might maximize clinical response and minimize adverse effects. Genetic polymorphisms in the thiopurine S-methyl transferase (TPMT) gene have been associated with decreased TPMT activity and the development of myelotoxicity due to high thioguanine metabolite concentrations. 3,4 Moreover, inosine triphosphate pyrophosphatase (ITPA) deficiency has recently been associated with AZA toxicity because of the accumulation of 6-thioinosine-triphosphate. 5,6 Theoretically, low TPMT activity might also augment the therapeutic efficacy of thiopurines and lead to better long-term clinical outcomes. To confirm the usefulness of the TPMT/ITPA genotype or TPMT activity in clinical prediction, research regarding the relevance of measurement for prevention of both adverse effects and clinical outcomes is necessary. However, the impact of the TPMT/ITPA genotype on long-term clinical response of IBD patients treated with AZA/6-MP has not yet been examined. In this study, we investigated whether TPMT/ ITPA genotypes could affect long-term clinical outcomes as measured by disease relapse in Korean patients with IBD undergoing AZA or 6-MP treatment. MATERIALS AND METHODSA total of 204 patients with IBD (105 patients with Crohn's disease, 59 with ulcerative colitis and 40 with intestinal Behcet's disease) were initiated on AZA treatment during the s...

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Section: Discussionmentioning

confidence: 99%

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

et al. 2009

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“…40 Genetic alterations in the ITPase gene, and thus a decreased ITPase activity, are associated with adverse outcomes of conventional thiopurine therapy, probably by the accumulation of 6-thioinosine-triphosphate (6TITP). 41,42 Since 6TITP is a substrate for TPMT, accumulation of 6TITP may result in accumulation of 6-MMPR (Fig. 1).…”

Section: 29mentioning

confidence: 99%

The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: Results from a prospective pharmacological study

Seinen

Asseldonk

Boer

et al. 2013

Journal of Crohn's and Colitis

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Introduction: Thiopurine therapy is often discontinued in inflammatory bowel disease (IBD) patients. The xanthine oxidase (XO) inhibitor allopurinol has previously shown to enhance thiopurine efficacy and to prevent adverse reactions, the mechanism of this beneficial interaction is not completely clarified. The aim of this study is to observe possible effects of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes. Methods: A prospective study of IBD patients failing thiopurine therapy due to a skewed thiopurine metabolism was performed. Patients were treated with allopurinol and azathioprine or mercaptopurine. Xanthine oxidase, hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and thiopurine S-methyl transferase (TPMT) activities, and thiopurine metabolites concentrations were measured during thiopurine monotherapy, and after 4 and 12 weeks of combination therapy. Conclusion: Allopurinol and thiopurine combination-therapy seems to increase HGPRT and decrease XO activity in IBD patients, which at least in part may explain the observed changes in thiopurine metabolite concentrations.

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“…A recent prospective British study in IBD patients (n ¼ 207) found that similar to TPMT deficiency, ITPA deficiency (both determined by genotyping) was also a predictor of AZA adverse effects. 34 Notably, this study also reported that carrying a heterozygous TPMT genotype strongly predicted adverse effects (79% heterozygous vs 35% wild-type TPMT, Po0.001). These observations suggest that taking into considerations the benefits for carriers of heterozygous TPMT alleles may substantially improve the overall cost-effectiveness of TPMT genotyping for patients prescribed AZA.…”

Section: Methodsmentioning

confidence: 73%

Improving pharmacovigilance in Europe: TPMT genotyping and phenotyping in the UK and Spain

et al. 2009

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Thiopurine S-methyltransferase (TPMT) is the rate-limiting step in the conversion of thiopurine drugs including azathioprine (AZA) to inactive metabolites. Heritable deficiency of TPMT activity increases risk for adverse events, most notably, myelosuppression leading to leukopenia and neutropenic sepsis. The reported European Commission study was undertaken to identify current evidence for the clinical utility of testing for TPMT status and extent of uptake, by either genotyping or phenotyping, in the clinical setting. Data presented here for the UK and Spain indicate that there has been a considerable increase in the uptake of TPMT testing in recent years. There are some data that support routine TPMT testing before AZA prescribing for reducing AZA-related adverse events. Key data include evidence in favor of TPMT testing in addition to the current practice of routine monitoring for reducing the number of AZA-related episodes of myelosuppression, averting deaths from neutropenic sepsis and improving health-related quality of life. Further data are needed for determining the cost-effectiveness of routine TPMT testing.

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Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease

Abstract: SUMMARY BackgroundOne-third of patients with inflammatory bowel disease (IBD) receiving azathioprine (AZA) withdraw treatment due to side effects or lack of clinical response.

Cited by 153 publications

References 56 publications

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

Correlation of genotypes for thiopurine methyltransferase and inosine triphosphate pyrophosphatase with long-term clinical outcomes in Korean patients with inflammatory bowel diseases during treatment with thiopurine drugs

The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: Results from a prospective pharmacological study

Improving pharmacovigilance in Europe: TPMT genotyping and phenotyping in the UK and Spain

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