Weight and Body Composition Compartments do Not Predict Therapeutic Thiopurine Metabolite Levels in Inflammatory Bowel Disease

Abstract

OBJECTIVES:Thiopurine drugs are the most commonly used steroid-sparing therapies in moderate-to-severe inflammatory bowel disease (IBD). Their complex metabolism and their narrow therapeutic windows means that optimal dosing is difficult. However, weight-based dosing is the norm. Similar antimetabolites are dosed by body composition parameters. In IBD, treatment response and toxicity has been shown to correlate with thiopurine metabolite levels. We sought to determine whether weight or body composition parameters predicted therapeutic 6-thioguanine nucleotide (6TGN) or toxic 6-methylmercaptopurine (6MMP) levels.METHODS:This single-center retrospective cohort study identified 66 IBD patients who had body composition analysis and thiopurine metabolite levels tested. Statistical analysis was performed using Spearman correlation, Kruskal–Wallis, Mann–Whitney, and unpaired t tests and receiver-operator operating characteristic curves. A P value of <0.05 was considered significant.RESULTS:No correlation was identified between 6TGN and any body composition parameters, absolute drug dose or drug dose/kg of fat mass, fat-free mass (FFM), subcutaneous adipose tissue area, or visceral adipose tissue area. However, 6MMP correlated with azathioprine dose, thiopurine dose/kg of body weight, and with several body composition parameters.CONCLUSIONS:No relationship was found between therapeutic metabolite levels and weight or body composition compartments. Higher thiopurine doses, especially in relation to FFM, are associated with higher levels of potentially hepatotoxic 6MMP and shunting toward this metabolite. Conventional weight-based dosing to attain therapeutic metabolite levels appears unreliable and may be replaced by metabolite level testing.

The impact of body mass index on efficacy and safety in the tofacitinib OCTAVE ulcerative colitis clinical programme

“…In contrast, BMI was found to have no effect on rates of remission among patients with Crohn’s disease receiving ustekinumab maintenance therapy 17 . In addition, an analysis of the thiopurines azathioprine and mercaptopurine, which are dosed based on body weight, showed that therapeutic metabolite levels in patients with UC and Crohn’s disease were not related to weight or body composition compartments 18 . Together, these findings suggest that further research is required to better understand the impact of obesity on the efficacy of UC treatment and possible consequences of dosing regimens.…”

“…17 In addition, an analysis of the thiopurines azathioprine and mercaptopurine, which are dosed based on body weight, showed that therapeutic metabolite levels in patients with UC and Crohn's disease were not related to weight or body composition compartments. 18 Together, these findings suggest that further research is required to better understand the impact of obesity on the efficacy of UC treatment and possible consequences of dosing regimens. Obesity is a known risk factor for reduced response to vaccines and for infection, 21,22 and in OCTAVE Induction 1 and 2 there was a numerically higher rate of serious infections and NMSC in the baseline BMI ≥30 subgroup treated with tofacitinib 10 mg b.d.…”

The Role of Adipose Tissue in the Pathogenesis and Therapeutic Outcomes of Inflammatory Bowel Disease

“…In this respect, there exists an association between the level of 6-thioguanine nucleotide (6-TGN), an azathioprine therapeutic metabolite, and clinical remission [127]. Holt et al [128] used cross-sectional CT imaging to investigate if body composition could provide more accurate means of achieving therapeutic levels of 6-TGN. They found no relationship between therapeutic levels of 6-TGN and subcutaneous or visceral fat, suggesting that the distribution of fat has little impact on thiopurine therapy.…”

Can visceral adipose tissue and skeletal muscle predict recurrence of newly diagnosed Crohn’s disease in different treatments

“…The metabolite of immunosuppressants such as azathioprine was 6-thioguanine nucleotide (6-TGN) which are related to the effect of CD remission [ 31 ]. Holt et al demonstrated that VAT area and SAT area had no association the level of 6-TGN [ 32 ]. This may explain the reason why MFI was not related to the recurrence.…”