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Randomized Controlled Trial
. 2017 Oct;23(10):1873-1881.
doi: 10.1097/MIB.0000000000001163.

More Dose-dependent Side Effects with Mercaptopurine over Azathioprine in IBD Treatment Due to Relatively Higher Dosing

Mark M T J Broekman  1 , Marieke J H Coenen, Corine J van Marrewijk, Geert J A Wanten, Dennis R Wong, Andre L M Verbeek, Olaf H Klungel, Piet M Hooymans, Henk-Jan Guchelaar, Hans Scheffer, Luc J J Derijks, Dirk J de Jong; TOPIC Recruitment Team
Affiliations
Randomized Controlled Trial

More Dose-dependent Side Effects with Mercaptopurine over Azathioprine in IBD Treatment Due to Relatively Higher Dosing

Mark M T J Broekman et al. Inflamm Bowel Dis. 2017 Oct.

Abstract

Background: There are substantial global differences in the preference for mercaptopurine (MP) or its prodrug azathioprine (AZA) as first-choice thiopurine to treat inflammatory bowel diseases. Studies comparing both agents are scarce. Our aim was to compare AZA and MP in thiopurine-naive patients with inflammatory bowel disease for the frequency of side effects and efficacy.

Methods: Post hoc analysis of the "Thiopurine response Optimization by Pharmacogenetic testing in Inflammatory bowel disease Clinics" (TOPIC) trial, in which thiopurine-naive patients with inflammatory bowel disease with an indication for a thiopurine were randomized for a genotype-based dose versus standard of care. For this study, Cox proportional hazard ratios (HRs) were calculated to compare AZA and MP for discontinuation rates within 5 months, incidence of hepatotoxicity, leukopenia, and gastrointestinal side effects. Treatment efficacy was compared by logistic regression.

Results: Patient characteristics were similar for patients treated with AZA (n = 494, 64.4%) and MP (n = 273, 35.6%), yet patients with MP were relatively higher dosed compared with those on AZA. Discontinuation rates within 5 months were not different, 39.3% (AZA) and 38.1% (MP), HR 0.92 (95% confidence interval, 0.72-1.17; P = 0.50); however, patients on MP were more often subjected to dose reductions (30% versus 14%, P < 0.01). Higher rates of hepatotoxicity, HR 1.93 (95% confidence interval, 1.35-2.76; P < 0.01) and leukopenia, HR 2.55 (95% confidence interval, 1.51-4.30; P < 0.01) were observed with MP, which annulled in a secondary analysis with adjustment for the higher dose and metabolite levels.

Conclusions: Patients treated with MP were relatively higher dosed, which resulted in more dose-dependent side effects and a higher rate of dose reductions.

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Conflict of interest statement

The authors have no conflict of interest to disclose.

Figures

FIGURE 1.
FIGURE 1.
Time to treatment discontinuation for patients assigned to AZA and MP. No difference in treatment discontinuation was observed between AZA and MP, P = 0.57.
FIGURE 2.
FIGURE 2.
Time to development of signs of hepatotoxicity (defined as more than 2 times the ULN increase of ALT or conjugated bilirubin, or a combined increase in AST and alkaline phosphatase provided that one of them is above 2 times the ULN) in patients taking AZA or MP. No difference was observed in the time to the development of signs of hepatotoxicity between AZA and MP (P = 0.64).
FIGURE 3.
FIGURE 3.
Maximum increase in ALT in units/litre compared with baseline in patients on AZA (n = 59) and patients on MP (n = 62) who developed signs of hepatotoxicity. No difference was observed between AZA and MP (P = 0.83).
FIGURE 4.
FIGURE 4.
Time to development of leukopenia (defined as a white blood cell count ≤3.0 × 109/L) in patients taking AZA or MP. No difference was observed between patients on AZA and MP (P = 0.62).
FIGURE 5.
FIGURE 5.
Time to development of gastrointestinal side effects in patients taking AZA or MP. No difference was observed between AZA and MP (P = 0.52).
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