Tag Archives: 6-TG

Thiopurine Metabolite Testing -NASPGHAN Consensus Recommendations

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The inflammatory bowel disease committee of NASPGHAN has published a review and recommendations for the use of thiopurine metabolite testing (JPGN 2013; 56: 333-40).

The effectiveness of thiopurines is reviewed with a few key points:

  • Cochrane reviews have shown that azathioprine and 6-mercaptopurine are effective in inducing remission in Crohn’s disease.  For active disease the overall response rate has been reported as 54% compared with 33% for placebo.
  • For ulcerative colitis, a Cochrane analysis deemed the methodologic quality of 4 of the 6 studies as unsatisfactory and that all studies were small.  “The reviewers concluded that azathioprine may be effective treatment for patients with ulcerative colitis.”

The review covers the potential adverse effects of the thiopurines: myelosuppression, pancreatitis, elevated transaminases, susceptibility to infection, and malignancy.  The review suggests that the risk of non-Hodgkin lymphoma is probably increased up to 4-fold. Though, it is difficult to determine how much of the risk is truly due to the usage of thiopurines or other confounding factors.  The studies about the risk of non-melenoma skin cancer are not discussed.

Other covered topics: advantages of thiopurine metabolite testing (6-thioguanine [6-TGN] and 6-methylmercaptopurine[ 6-MMP]), potential disadvantages of metabolite testing (e.g.. cost), use of genotype versus phenotype (phenotypic testing is generally preferred), thiopurine metabolism, devising target levels, use of allopurinol, and misinterpretation of metabolite testing.

Specific Consensus Recommendations:

  • Obtain thiopurine methyltransferase (TPMT) testing prior to initiation of thiopurines.
  • Avoid use of thiopurines in individuals with extremely low TPMT activity or who are homozygous recessive for TPMT activity
  • TPMT testing does not predict all cases of leukopenia.  All individuals receiving thiopurines should have routine monitoring with CBCs.  “Most adverse effects from thiopurines are not directly related to 6-TGN or 6-MMP levels.”
  • Metabolite testing can help determine adherence to therapy
  • Metabolite testing may be helpful in guiding dose adjustment and/or adding allopurinol treatment
  • Routine and repetitive testing of metabolites is not recommended in patients who are doing well on an acceptable thiopurine dosage.

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Natural laws not patentable: the case with Prometheus

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While most individuals might think of greek mythology or the recent movie when hearing the word “Prometheus,” pediatric gastroenterologists might think of the company that performs a number of useful diagnostic tests.  Recently, Prometheus has had a legal setback (NEJM 2012; 365: 2338-40). 

Since the 1990s, Prometheus has tested for azathioprine (& 6-mercaptopurine) metabolites.  A therapeutic level of 6-thioguanine (6-TG), a metabolite for these drugs, is recognized as generally between 230-400 pmol per 8×10(to the 8th) red cells.  Levels outside this range often require drug adjustments.

When the Mayo clinic started to offer a slightly different assay, priced 25% below Prometheus’s test, Prometheus sued for patent infringement.  The court held that “if a law of nature is not patentable, then neither is a process reciting a law of nature;”  hence, Prometheus’s patent was rejected.

There are implications of this lawsuit on the use of a large number of biomarkers.  For example, patents for BRCA DNA sequences that increase the risk for cancer will probably be overturned.  Industry groups argue that denying patents will halt progress as companies will not be able to recoup investments in biomarker development.  Congress could consider passing laws allowing exclusive marketing of these innovations.  Alternatively, adequate funding through the NIH (National Institutes of Health) could allow development of biomarkers without the need for patents; in fact, 100 projects are in progress at this time.