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Thiopurines
van Asseldonk, D.P.
2015
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van Asseldonk, D. P. (2015). Thiopurines: Improving treatment of inflammatory bowel disease.
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Dirk P van Asseldonk Nanne K de Boer Adriaan A van Bodegraven
Aliment Pharmacol Ther 2011;34(8):1039-9. Letter to the Editor
THIOPURINE METABOLITE MEASUREMENT
– NOT FOR EVERYONE
6
THIOPURINE METABOLITE MEASUREMENT – NOT FOR EVERYONE
SIRS, Measurement of thiopurine metabolites is currently widely available, but its clinical usefulness has been debated1,2. Gonzales-Lama et al. reported about the relation between
thiopurine metabolite concentrations and clinical response in IBD patients3. When
comparing patients in corticosteroid-free clinical remission with patients who did not respond favourably (steroid dependency, additional medical or surgical treatment), or experienced adverse events during thiopurine treatment, no difference in 6-thioguanine nucleotide (6-TGN) concentrations was observed. In addition, prediction of beneficial outcome using the previously proposed 6-TGN threshold value of 230 pmol/8x10^8 red blood cells was poor. In our opinion, these results are difficult to interpret. IBD is characterised by a relapsing and remitting course, contributing to high placebo-response rates in clinical trials4. Distinguishing
between a therapeutic beneficial response due to therapy or due to a natural course is difficult, whatever the metabolite levels may be. As pharmacodynamics and pharmacokinetics are not directly associated, it is unsurprising that the clinical assessment of outcome is not necessarily related to 6-TGN concentrations. On the other hand, accounting for the low specificity of 6-TGN metabolite measurement, patients can actually be thiopurine refractory despite having allegedly therapeutic 6-TGN concentrations (table 1). In addition to this important limitation of routine thiopurine metabolite measurement, other methodological concerns exist. First, chemical stability of 6-TGN is limited and influenced by storage temperature, hence sampling and processing conditions are of major influence on concentrations being measured5. Second,
6-TGN is measured in red blood cells, which are a surrogate for the actual target cells – the leucocytes. Nevertheless, although not prospectively confirmed, a thiopurine metabolite- directed algorithm was recently shown to be beneficial2. Moreover, patients exhibiting a skewed
thiopurine metabolism (low 6-TGN and high 6-methyl mercaptopurine concentrations), which frequently coincides with adverse events or therapeutic resistance, can profit from drug modification, e.g. allopurinol co-treatment6. In conclusion, thiopurine metabolites have limited
value in predicting response when determined routinely in all thiopurine-using patients, but remain valuable in case of refractory disease or to counteract adverse events.
The presence of two different subgroups of patients hampers the routine use of 6-thioguanine nucleotide (6-TGN) measurement. As a result of the relapsing course of IBD, a clinical response can be observed even if 6-TGN concentrations are below the allegedly therapeutic concentration (C). In addition, patients can actually be unresponsive despite adequate 6-TGN, suggestive of a contrast between pharmacokinetic parameters and the actual pharmacodynamic effect (B). Ideally, there would only be nonresponsive patients with sub-therapeutic 6-TGN (D) and responsive patients with sub-therapeutic 6-TGN concentrations (A).
Table 1. Possible outcomes with routine thiopurine metabolite measurement
Response Nonresponse
Therapeutic [6-TGN] A B A+B
Sub-therapeutic [6-TGN] C D C+D
A+C B+D Total
REFERENCES
1 Reinshagen M, Schutz E, Armstrong VW, Behrens Cm Von Tirpitz C, et al. 6-thioguanine nucleotide-adapted azathioprine therapy does not lead to higher remission rates than standard therapy in Crohn’s disease: result from a randomized, controlled, open trial. Clin Chem. 2007;53:1306-14.
2 Haines ML, Ajlouni Y, Irving PM, Sparrow MP, Rose R, et al. Clinical usefulness of therapeutic drug monitoring of thiopurines in patients with inadequately controlled inflammatory bowel disease. Inflamm Bowel Dis. 2011;17:1301-7. 3 Gonzalez-Lama Y, Bermejo F, Lopez-Sanroman
A, Lopez-Sanroman A, Gaercia-Sanchez V, et al. Thiourine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated
inflammatory bowel disease patients. Aliment Pharmacol Ther. 2011;34:544-54.
4 Sands BE. The placebo response rate in irritable bowel syndrome and inflammatory bowel disease. Dig Dis. 2009;27(Suppl.1):68-75. 5 De Graaf P, Vos RM, De Boer NK, Sinjewel A,
Jharap B, et al. Limited stability of thiopurine metabolites in blood samples relevant in research and clinical practice. J Chromatogr B Analyt technol Biomed Life Sci. 2010;878:1437-42. 6 Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol. 2007;5:209-14.
