Firm recommendations about the way thiopurine drugs are being introduced.
However, the use of thiopurine methyltransferase and metabolite measurements during treatment in inflammatory bowel disease (IBD) are lacking.
Dr Ulf Hindorf and colleagues evaluated pharmacokinetics and tolerance after initiation of thiopurine treatment with a fixed dosing schedule in patients with IBD.
The team assessed 60 consecutive patients in a 20 week open, prospective study, of which 33 had Crohn's disease and 27 had ulcerative colitis.
Thiopurine treatment was introduced using a predefined dose escalation schedule.
The daily target dose at week 3 was 2.5 mg azathioprine or 1.25 mg 6-mercaptopurine per kg body weight.
|67% with adverse events tolerated long term treatment on a lower dose|
Thiopurine methyltransferase and genotypes, thiopurine methyltransferase activity, gene expression, and metabolites were determined.
The investigative team monitored clinical outcome and occurrence of adverse events.
The team reported that 27 patients completed the study per protocol, while 33 were withdrawn.
Of those patients withdrawn, 5 had early protocol violation, thiopurine methyltransferase deficiency occurred in 1, and 27 had adverse events.
The team noted that 67% of patients with adverse events tolerated long term treatment on a lower dose, a median 1.32 mg azathioprine/kg body weight.
Thiopurine methyltransferase activity did not change during the 20 week course of the study.
However, the team found a significant decrease in thiopurine methyltransferase gene expression.
Patients with methylthioinosine monophosphate concentrations more than 11,450 pmol/8x108 red blood cells at week 5 had an increased risk of myelotoxicity.
Dr Hindorf's team commented, “After initiation of thiopurine treatment using a fixed dosing schedule, no general induction of thiopurine methyltransferase enzyme activity occurred, though gene expression decreased.”
“The development of different types of toxicity was unpredictable, but we found that measurement of methylthioinosine monophosphate early in the steady state phase helped to identify patients at risk of developing myelotoxicity.”