Departments of *Gastroenterology, †Human Genetics, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; ‡Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen, the Netherlands; §Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands; ‖Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, the Netherlands; ¶Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands; and **Department of Clinical Pharmacy, Máxima Medical Center, Veldhoven, the Netherlands.
Inflamm Bowel Dis. 2017 Oct;23(10):1873-1881. doi: 10.1097/MIB.0000000000001163.
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.
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.
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.
Patients treated with MP were relatively higher dosed, which resulted in more dose-dependent side effects and a higher rate of dose reductions.
在治疗炎症性肠病时，巯嘌呤（MP）或其前体药物硫唑嘌呤（AZA）作为首选硫嘌呤的选择在全球范围内存在很大差异。比较这两种药物的研究很少。我们的目的是比较炎症性肠病初治患者中 AZA 和 MP 的副作用和疗效。
对“炎症性肠病临床中通过遗传药理学检测优化硫嘌呤反应（TOPIC）”试验进行事后分析，该试验将有硫嘌呤治疗指征的炎症性肠病初治患者随机分为基于基因型的剂量与标准治疗。对于这项研究，计算了 Cox 比例风险比（HRs），以比较 5 个月内 AZA 和 MP 的停药率、肝毒性、白细胞减少和胃肠道副作用的发生率。通过逻辑回归比较治疗效果。
接受 AZA（n = 494，64.4%）和 MP（n = 273，35.6%）治疗的患者的患者特征相似，但 MP 组患者的剂量相对较高。5 个月内的停药率无差异，分别为 39.3%（AZA）和 38.1%（MP），HR 0.92（95%置信区间，0.72-1.17；P = 0.50）；然而，MP 组患者更频繁地进行剂量减少（30%对 14%，P < 0.01）。MP 组肝毒性发生率较高，HR 1.93（95%置信区间，1.35-2.76；P < 0.01）和白细胞减少症发生率较高，HR 2.55（95%置信区间，1.51-4.30；P < 0.01），但在调整更高剂量和代谢物水平的二次分析中，这些差异被消除。
接受 MP 治疗的患者相对较高剂量，这导致更多剂量依赖性副作用和更高的剂量减少率。
