Effectiveness and safety of thiopurines in inflammatory bowel disease patients with NUDT15 polymorphism: a real-world retrospective study.

IF 3.6 3区医学 Q2 PHARMACOLOGY & PHARMACY

Expert Review of Clinical Pharmacology Pub Date : 2025-03-01 Epub Date: 2025-02-11 DOI:10.1080/17512433.2025.2465425

Abhirup Chatterjee, Prateek Bhatia, Saroj K Sinha, Anupam K Singh, Harshal S Mandavdhare, Jimil Shah, Vaneet Jearth, Arpit Sasani, Aravind Sekar, Minu Singh, Usha Dutta, Vishal Sharma

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引用次数: 0

Abstract

Background: Thiopurine S-methyltransferase (TPMT) and Nudix hydrolase (NUDT15) polymorphisms predispose to thiopurine-related leukopenia.

Methods: Retrospective evaluation of inflammatory bowel disease (IBD) patients harboring NUDT15 polymorphisms and exposed to thiopurines. We report the frequency of NUDT15 polymorphism, frequency of leukopenia, the tolerated dose of azathioprine, and the clinical efficacy of thiopurines.

Results: Of 1440 patients, 118 (8.2%) had NUDT15 polymorphism. Among 51 with complete details, 46 were heterozygous (90.2%), and 5 homozygous (9.2%) for NUDT15. Twenty (43.5%) heterozygous and all homozygous patients developed leukopenia. Leukopenia was significantly more in NUDT15 heterozygous group compared to controls (43.45% vs 7.8%, Odds ratio: 9, 95% CI 3.57-22.9). The maximum tolerated dose of azathioprine was lower in NUDT15 heterozygous group (1.1 ± 0.4 mg per kg vs 1.7 ± 0.7 mg per kg, p = 0.002). The mean time to leukopenia was earlier in the heterozygous group vs controls (19 ± 56 weeks vs 70 ± 53 weeks, p-value 0.002). Seven (35%) of 20 heterozygous patients who developed leukopenia, could be maintained at a lower dose of thiopurine. Twenty-five maintained clinical remission while on thiopurines.

Conclusion: Thiopurines should be avoided in NUDT15 homozygous but can be used cautiously at lower dosages with frequent monitoring among heterozygous patients.

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硫嘌呤治疗NUDT15多态性炎症性肠病患者的有效性和安全性：一项真实世界的回顾性研究

背景：硫嘌呤s -甲基转移酶（TPMT）和Nudix水解酶（NUDT15）多态性易导致硫嘌呤相关的白细胞减少症。方法：回顾性评估携带NUDT15多态性并暴露于硫嘌呤的炎症性肠病（IBD）患者。我们报道了NUDT15多态性的频率、白细胞减少的频率、硫嘌呤的耐受剂量以及硫嘌呤的临床疗效。结果：1440例患者中，118例（8.2%）存在NUDT15多态性。51个完整基因中，NUDT15为杂合基因46个（90.2%），纯合基因5个（9.2%）。20例（43.5%）杂合子和所有纯合子患者发生白细胞减少。NUDT15杂合组白细胞减少率明显高于对照组（43.45% vs 7.8%，优势比：9,95% CI 3.57 ~ 22.9）。NUDT15杂合组硫唑嘌呤的最大耐受剂量较低（1.1±0.4 mg / kg vs 1.7±0.7 mg / kg, p = 0.002）。杂合子组出现白细胞减少的平均时间比对照组早（19±56周比70±53周，p值为0.002）。20例发生白细胞减少的杂合子患者中有7例（35%）可以维持较低剂量的硫嘌呤。25人在服用硫嘌呤后仍保持临床缓解。结论：NUDT15纯合子患者应避免使用硫嘌呤类药物，但在杂合子患者中可谨慎小剂量使用并经常监测。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Expert Review of Clinical Pharmacology PHARMACOLOGY & PHARMACY-

CiteScore

7.30

自引率

2.30%

发文量

127

期刊介绍： Advances in drug development technologies are yielding innovative new therapies, from potentially lifesaving medicines to lifestyle products. In recent years, however, the cost of developing new drugs has soared, and concerns over drug resistance and pharmacoeconomics have come to the fore. Adverse reactions experienced at the clinical trial level serve as a constant reminder of the importance of rigorous safety and toxicity testing. Furthermore the advent of pharmacogenomics and ‘individualized’ approaches to therapy will demand a fresh approach to drug evaluation and healthcare delivery. Clinical Pharmacology provides an essential role in integrating the expertise of all of the specialists and players who are active in meeting such challenges in modern biomedical practice.