Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease

Abstract

Background: Firm recommendations about the way thiopurine drugs are introduced and the use of thiopurine methyltransferase (TPMT) and metabolite measurements during treatment in inflammatory bowel disease (IBD) are lacking. Aim: To evaluate pharmacokinetics and tolerance after initiation of thiopurine treatment with a fixed dosing schedule in patients with IBD. Patients: 60 consecutive patients with Crohn's disease (n = 33) or ulcerative colitis (n = 27) were included in a 20 week open, prospective study. Methods: Thiopurine treatment was introduced using a predefined dose escalation schedule, reaching a daily target dose at week 3 of 2.5 mg azathioprine or 1.25 mg 6-mercaptopurine per kg body weight. TPMT and ITPA genotypes, TPMT activity, TPMT gene expression, and thiopurine metabolites were determined. Clinical outcome and occurrence of adverse events were monitored. Results: 27 patients completed the study per protocol, while 33 were withdrawn (early protocol violation (n = 5), TPMT deficiency (n = 1), thiopurine related adverse events (n = 27)); 67% of patients with adverse events tolerated long term treatment on a lower dose (median 1.32 mg azathioprine/kg body weight). TPMT activity did not change during the 20 week course of the study but a significant decrease in TPMT gene expression was found (TPMT/huCYC ratio; p = 0.02). Patients with meTIMP concentrations .11 450 pmol/8610 8 red blood cells during steady state at week 5 had an increased risk of developing myelotoxicity (odds ratio = 45.0; p = 0.015). Conclusions: After initiation of thiopurine treatment using a fixed dosing schedule, no general induction of TPMT enzyme activity occurred, though TPMT gene expression decreased. The development of different types of toxicity was unpredictable, but we found that measurement of meTIMP early in the steady state phase helped to identify patients at risk of developing myelotoxicity.

Thiopurine Drugs Azathioprine and 6-Mercaptopurine Inhibit Mycobacterium paratuberculosis Growth In Vitro

“…Phase II, designed based on the results of phase I, used seven clinical strains of M. paratuberculosis of bovine or human origin and one M. avium strain, ATCC 35712, as a control. Some drugs to which M. paratuberculosis was not susceptible in phase I, specifically the SS drug family (SS, 5-ASA, and SP), were excluded, and AZA, a prodrug of 6-MP, was added to the trial (19,27).…”

6-Thioguanine Nucleotide–Adapted Azathioprine Therapy Does Not Lead to Higher Remission Rates Than Standard Therapy in Chronic Active Crohn Disease: Results from a Randomized, Controlled, Open Trial

“…The quality of life measured by the IBDQ increased in the standard group from mean (SD) 132 (30) at Ϫ2 weeks to 187 (20) at week 16 and 172 (32) at week 24 [not significant (NS]. In the dose-adapted group, the IBDQ increased from 140 (33) at Ϫ2 weeks to 194 (21) at week 16 and 196 (20) at week 24 (NS).…”

“…Increased concentrations of 6-MMP have been implicated in the pathogenesis of AZA-induced hepatotoxicity (10 ) and myelotoxicity (20 ). It was suggested that 6-MMP concentrations Ͻ5700 pmol/8 ϫ 10 8 Ery were less often associated with increased transaminase activities (10 ).…”

Mercaptopurine treatment should be considered in azathioprine intolerant patients with inflammatory bowel disease

“…The potential influences of TPMT and ITPA polymorphisms have gained interest during the last years and several studies have demonstrated that myelotoxicity is a dose-dependent phenomenon that often can be attributed to a low TPMT activity and ⁄ or high metabolite concentrations. 16,32 These insights into thiopurine metabolism have not resulted in a better understanding of the mechanisms behind early, doseindependent or idiosyncratic toxicity, like digestive intolerance, flu-like reactions and pancreatitis. TP-induced pancreatitis is generally considered as an idiosyncratic reaction in which a re-challenge with another or the same thiopurine drug will inevitably result in a new episode of pancreatitis.…”