P537 Weight and body composition compartments do not predict thiopurine metabolite levels
D. Holt*1, B. Strauss2, G. Moore1, 2
1Monash Health, Department of Gastroenterology & Hepatology, Clayton, Australia, 2Monash University, School of Clinical Sciences, Melbourne, Australia
Azathioprine and its metabolite, 6-mercaptopurine, are foundations of steroid-sparing therapy in moderate-to-severe inflammatory bowel disease. Further, 50%–60% of patients respond to these treatments; the remainder will have refractory disease or adverse drug reactions. The complex metabolism of these drugs and their narrow therapeutic windows mean that optimal dosing is difficult. Measurement of intracellular thiopurine metabolites has led to the development of treatment algorithms based on therapeutic 6-thioguanine nucleotide (6TGN) and toxic 6-methylmercaptopurine (6MMP) levels, with an association between levels of 6TGN and likelihood of clinical response. However, weight-based dosing remains the norm, with measurement of thiopurine metabolites often reserved for those who fail to respond to therapy. Importantly, there are no published data regarding thiopurine metabolite levels and body composition parameters. We sought to determine whether dosing by weight, or another component of body composition, might predict thiopurine metabolite levels and permit more appropriate induction dosing of these medications.
A retrospective cohort study identified 59 patients from a single tertiary teaching hospital as having had thiopurine metabolite levels tested during therapy with azathioprine within a 12-month period of body composition studies performed by either whole-body DXA, or analysis of cross-sectional abdominal CT or MRI scan. Available body composition and anthropometry data included weight, height, body mass index, body surface area, appendicular skeletal muscle index, appendicular muscle mass, total body fat-free mass, total body fat mass, percentage body fat, trunk lean tissue mass, trunk fat mass, android fat mass, gynoid fat mass, and waist circumference. Azathioprine dose, erythrocyte concentrations of 6TGN, 6MMP, and the ratio between these 2 measures were reported.
There was no significant correlation between any measures of body composition and metabolite levels. Using previously defined categories of thiopurine metabolites, subjects were classified as having either: 1. Therapeutic 6TGN; 2. Sub-therapeutic 6TGN; or 3. Ratio 6MMP:6TGN >20. Between these categories, there was no difference in dose of azathioprine per kilogram of body weight, dose/kg of fat mass, dose/kg of fat free mass, or weight alone. Clinical response was not recorded in this cohort.
Interestingly, the dose of azathioprine per kilogram of body weight, the accepted method of dosing azathioprine in inflammatory bowel disease, did not predict whether subjects were likely to have metabolites in the therapeutic range. Arbitrary initial dosing of thiopurines with subsequent dosing by metabolite level testing may replace weight-based dosing.