Commentary: individual vs. weight‐based dosing of azathioprine in Crohn's disease

Abstract

This study illustrates the difficulties of running a clinical study. There were several attempts to change the protocol, but low enrolment numbers resulted in an underpowered negative study. The primary end point of this study was clinical remission at 16 weeks. There was no difference in remission rates at 16 weeks, although the per-protocol analysis showed a trend towards better results in the individualised group (clinical remission in 3/12 in weight-based vs. 9/15 in the individualised group). These remission rates were below predicted levels, partly because a high proportion of patients had steroid dependency or steroid-refractory disease. The secondary outcomes were remission at 28 and 52 weeks, but only 4 patients were still in the study at week 52. This study shows that dose escalation does not always achieve the target concentration. For the individualised group, the mean 6-tioguanine (thioguanine) (6TGN) concentrations among normal thiopurine methyltransferase (TPMT) metabolisers was 198 pmol/8 9 10 red blood cells (significantly below the therapeutic target of 250, and not different from the mean 6TGN for the weight-based arm). These disappointingly low 6TGN levels may also explain the low remission rates. This study adds to the data showing the clinical benefit of achieving higher 6TGN levels and is consistent with a meta-analysis of 6TGN and IBD activity. There was a significant difference in 6TGN between patients achieving remission and those not achieving remission (216 vs. 149), although a wide range and significant overlap in values were observed. The study showed a modest difference in dose between individualised and weight-based groups (3.4 compared with 2.3 mg/kg for normal TPMT and 1.5 compared with 2.4 mg/kg for intermediate levels), but the trial was not long enough to observe a more significant divergence. A study by Gardiner et al. showed a two-fold divergence in dosing after 9 months of monitoring and dose change, although they predicted that a three-fold difference was likely to be more appropriate. The most useful test may be the initial TMPT activity with reduction of starting dose to 1.0 – 1.5 mg/kg for patients with intermediate TPMT (in this study, the numbers with intermediate TMPT were low and it is difficult to reach any conclusions). The only similar study is a randomised, open-label study where dose adjustment was based on 6TGN alone. Recruitment was also difficult, and the numbers in each group were small. Similar to this study, mean concentrations of 6TGN were below target in the dose-adjusted group and not different from the weightbased group. It is difficult to see this study being repeated. The concept of dose optimisation of azathioprine dose is now well accepted, and there will be reluctance among clinicians to enrol patients into a weight-based arm. There is a strong body of data, including studies with azathioprine/allopurinol combination, supporting this approach. Dose optimisation may be a slow process and not easy to replicate in a clinical trial. However, the disappointing remission rates in this study should not discourage use of azathioprine for an extended period with dose optimisation.