When old drugs become new again - optimising thiopurine metabolism to improve clinical outcomes in patients with inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) comprises two diseases, Crohn’s disease and ulcerative colitis. The aims of medical therapy in IBD are to heal the bowel and prevent disability, leading to improved quality of life. For over thirty years, the mainstays of medical therapy for IBD are the thiopurines azathioprine (AZA) and 6-mercaptopurine (MP), which have been dosed based on an individual’s weight. Recent advances have led to the ability to measure the thiopurine metabolites: 6-thioguanine nucleotides (6TGN) and 6-methylmercaptopurine (6MMP). Previous research has shown that higher levels of 6TGN improve outcomes in the treatment of IBD and that high levels of 6MMP can cause side effects. It is also known that thiopurine metabolites do not correlate with weight-based dosing of drugs. Single centre, retrospective case series have also demonstrated that outcomes with thiopurines can be improved by optimising thiopurine metabolites via dose adjustments as well as the addition of allopurinol. Thiopurine adverse events can also be overcome using these techniques, however there are no prospective studies to determine the optimal methodology for manipulating thiopurine dosing. Until now, thiopurine dosage manipulations have been reactive to patients failing therapy. There is no published research examining the utility of early measurement of thiopurine metabolites to predict outcomes. This thesis encompasses three studies. The first is a quality assurance study to confirm that laboratories around Australasia are accurately measuring thiopurine metabolites. The second study was the Early Asssessment of Thiopurine Metabolites to Investigate the Changes in Thiopurine Metabolites and the 6-Methylmercaptopurine to 6-Thioguanine Ratio (EATME) Study. It was a single centre, prospective cohort study examining the measurement of thiopurine metabolites when patients are commenced on thiopurines using a dose escalation protocol. This study aimed to examine changes in thiopurine metabolites during dose escalation to determine if their measurement can be of predictive value. It also aimed to assess tolerability of thiopurines and the effectiveness of thiopurine manipulation to improve outcomes and minimise toxicity. The third study is the Use of Adjunctive Allopurinol in Azathioprine/6-Mercaptopurine Non-Responders to Optimise 6-Thioguanine Nucleotide Production and Improve Clinical Outcomes in Patients with Inflammatory Bowel Disease (AAA) study. It was a multicentre, prospective, double blind, dosing ranging study to examine the effect of two doses of allopurinol to optimise thiopurine metabolites in thiopurine hypermethylators (shunters) and improve clinical outcomes. It was demonstrated that Australasian laboratories accurately measure thiopurine metabolites. The EATME and AAA studies showed that the measurement of thiopurine metabolites during dose escalation can predict final, steady state levels and a predictive formula has been developed that requires further validation. Despite initial high rates of toxicity related to thiopurines, the majority of these can be overcome with thiopurine optimisation, leading to improved clinical outcomes. Finally, it was validated that low dose allopurinol in combination with reduced doses of thiopurines can reverse thiopurine hypermethylation, leading to significant improvements in clinical outcomes for patients without additional toxicity. In summary, measurement of thiopurine metabolites and subsequent optimisation of thiopurine metabolites via a number of techniques leads to significantly improved outcomes for patients with IBD. This is a significant advancement in the treatment of IBD given the limited, but improving medical armamentarium available to clinicians.