Thiopurines in Inflammatory Bowel Disease. New strategies for optimization of pharmacotherapy.


Dr. Luc JJ Derijks.
Promotores: Prof. dr. S.J.H. van Deventer en Prof. dr. C.J.J. Mulder. Co-promotores: Dr. L.G.J.B. Engels, Dr. D.W. Hommes, Dr. P.M. Hooymans.
One in every three inflammatory bowel disease (IBD) patients on thiopurines lacks efficacy and up 20% is forced to discontinue due to the occurrence of adverse events. In the past 10-20 years, knowledge of both thiopurine pharmacology and pharmacogenetics has increased dramatically leading to the development of new strategies to improve efficacy and reduce toxicity of thiopurines in IBD.
The overall goal of the research described in this thesis was to further increase basic knowledge of thiopurine pharmacology and determine whether or not the application of certain new strategies is an improvement in the management of IBD with thiopurines. These strategies included therapeutic drug monitoring (TDM), genotyping two crucial enzymes in thiopurine metabolism and the use of 6-thioguanine (6-TG) as such.
Thiopurine S-methyltransferase (TPMT) genotyping and TDM are useful instruments for individualizing thiopurine pharmacotherapy of IBD. TPMT genotyping before initiation of treatment prevents early and severe myelosuppression by identifying homozygous mutants. Furthermore, in case of TPMT heterozygosity, safety measures such as precautionary dose reductions can be taken. Subsequently, TDM can guide thiopurine dosing to optimal metabolite levels herewith reducing the risk of drug related toxicity and increasing the chance on drug efficacy. Furthermore, TDM is useful whenever non-compliance is suspected. Inosine triphosphate pyrophosphatase (ITPA) genotyping may be helpful in case of inexplicable myelotoxicity. At present, it is clear however that neither TDM nor TPMT or ITPA genotyping will replace or exclude frequent leukocyte monitoring in the screening for possible myelotoxicity.
In case of AZA- or 6-MP-intolerance, 6-TG seems a promising alternative. However, in the near future more knowledge needs to be gathered about its potential hepatotoxicity before it can be advocated or banned.