Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease

Background\ua0One-third of patients with inflammatory bowel disease (IBD) receiving azathioprine (AZA) withdraw treatment due to side effects or lack of clinical response.Aim\ua0 To investigate whether pharmacogenetic loci or metabolite concentrations explain clinical response or side effects to AZA.Methods\ua0 Patients with IBD were given 2\ua0mg/kg of AZA without dose escalation or adjustment. Serial clinical response, thiopurine methyl transferase (TPMT) activity and thioguanine nucleotide (TGN) concentrations were measured over 6\ua0months. All patients were genotyped for inosine triphosphatase (ITPase) and TPMT. Clinical response and side effects were compared to these variables.Results\ua0 Two hundred and seven patients were analysed. Thirty-nine per cent withdrew due to adverse effects. Heterozygous TPMT genotype strongly predicted adverse effects (79% heterozygous vs. 35% wild-type TPMT, P\ua0A mutation was associated with withdrawal due to flu-like symptoms (P\ua0=\ua00.014). A baseline TPMT activity below 35\ua0pmol/h/mg/Hb was associated with a greater chance of clinical response compared with a TPMT above 35\ua0pmol/h/mg/Hb (81% vs. 43% respectively, P\ua035\ua0pmol/h/mg/Hb). ITPase deficiency is a predictor of adverse effects and TGN concentrations above 100 correlate with clinical response