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Editor,—6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are effective in inflammatory bowel disease (IBD), mainly by their active 6-thioguanine (6-TG) metabolites. Efficacy and also myelotoxicity of 6-MP and AZA seem to be related to the 6-TG levels achieved. Instead of activation to 6-thioguanine nucleotides, 6-MP and AZA can be inactivated to 6-methylmercaptopurine (6-MMP) by the enzyme thiopurine methyltransferase (TPMT). High interindividual variability in TPMT activity is known. Therefore, measuring TPMT activity could be used to adjust the dose of 6-MP or AZA to reduce myelotoxicity. However, levels of 6-MMP formed by TPMT seem to correlate with toxicity.1
The issue in the commentary by Sandborn (
) was rational dosing of AZA and 6-MP.2 However, we would like to focus on direct administration of the active metabolite 6-TG. In a recent pilot study in IBD, patients treated with 6-TG had no methylated metabolites detected.3 6-TG dosing is feasible without measuring TPMT activity.
Following intravenous administration of 6-TG, pharmacokinetic behaviour is biphasic: a distribution half life of 15 minutes followed by a terminal half life of 11 hours. Oral absorption of 6-TG is approximately 30%. Administration by oral suspension is possible in which the suspension is stable for almost three months.46-TG tablets (Lanvis) have been available in our country since 1975 and registered for the treatment of acute and chronic myeloid leukaemia and acute lymphatic leukaemia.
We have started a prospective study of AZA or 6-MP in IBD patients with recurrent adverse events. The design is a non-randomised open label pilot study. The study medication will be 6-TG (Lanvis, Thioguanine Tabloid in the USA) in a starting dose of 40 mg orally per day.
The aim of the study is to obtain a clearer understanding of adverse events in conjunction with 6-TG serum levels in IBD, especially in patients with a history of skin rashes, fever, and pancreatitis related to AZA and 6-MP. Our first results are promising. However, we must evaluate 6-TG versus AZA and 6-MP in multicentre, prospective, randomised trials, leading up to FDA registration approval in the USA and Europe. Our major concern is that Glaxo Welcome is not interested as the drug is out of patent, similar to the situation with beclomethasone for IBD in the past.5
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