Department of Clinical Pharmacy, Clinical Pharmacology and Toxicology, Zuyderland Medical Centre, Sittard-Geleen/Heerlen, Netherlands.
Department of methodology and statistics, CAPHRI Care and Public Health Research Institute, Maastricht University Medical Center, Maastricht, Netherlands.
Br J Clin Pharmacol. 2024 Dec;90(12):3296-3307. doi: 10.1111/bcp.16219. Epub 2024 Aug 25.
Conventional thiopurines (azathioprine and mercaptopurine) remain standard therapy to maintain steroid sparing remission in inflammatory bowel disease (IBD), but are regularly discontinued due to adverse drug reactions (ADRs). Measurement of the metabolites 6-thioguanine nucleotides (6-TGN), 6-methylmercaptopurine ribonucleotides (6-MMPR) and the 6-MMPR/6-TGN ratio, may predict the development of these ADRs. Our aim was to evaluate whether early thiopurine metabolite measurements were associated with clinical outcomes.
A post-hoc analysis was conducted of a multicentre, prospective, observational study on thiopurine-induced hepatotoxicity. IBD patients who initiated thiopurine therapy were included and thiopurine metabolite concentrations were assessed after 7 days (±1) (T1). Patients were monitored for 12 weeks to document the occurrence of ADRs, early treatment discontinuation and effectiveness.
In total, 181 patients were evaluated. At T1, 6-MMPR concentrations and 6-TGN/6-MMPR ratios were independently related to treatment discontinuation within 12 weeks after correction for sex, age and body mass index (BMI) (P = .034 and .002, respectively). The largest effects were observed for 6-MMPR ≥3000 pmol/8 × 10 RBC and 6-TGN/6-MMPR ratio ≥17. Furthermore, 6-MMPR concentrations and 6-TGN/6-MMPR ratios at T1 were independently related to skewed metabolism at steady state (Week 8, 6-MMPR/-6TGN ratio ≥11 and ≥20) (both P < .001). The occurrence of ADRs and effectiveness were not independently related to T1 thiopurine metabolite concentrations.
Thiopurine metabolite concentrations at T1 were related to early treatment discontinuation and skewed metabolism at steady state, but not to effectiveness, helping to identify patients with a high risk of thiopurine treatment failure.
在炎症性肠病（IBD）中，传统的硫嘌呤（硫唑嘌呤和巯基嘌呤）仍然是维持类固醇缓解的标准治疗方法，但由于药物不良反应（ADR），它们经常被停用。测量代谢产物 6-硫鸟嘌呤核苷酸（6-TGN）、6-甲基巯基嘌呤核苷酸（6-MMPR）和 6-MMPR/6-TGN 比值，可预测这些 ADR 的发生。我们的目的是评估硫嘌呤代谢产物的早期测量是否与临床结局相关。
对一项关于硫嘌呤诱导肝毒性的多中心、前瞻性、观察性研究进行了事后分析。纳入开始使用硫嘌呤治疗的 IBD 患者，并在第 7 天（±1 天）（T1）评估硫嘌呤代谢产物浓度。监测患者 12 周，以记录 ADR 的发生、早期治疗停药和疗效。
共评估了 181 例患者。在校正性别、年龄和体重指数（BMI）后，T1 时 6-MMPR 浓度和 6-TGN/6-MMPR 比值与 12 周内治疗停药独立相关（P 值分别为.034 和.002）。6-MMPR ≥3000 pmol/8×10 RBC 和 6-TGN/6-MMPR 比值≥17 时观察到最大的效果。此外，T1 时 6-MMPR 浓度和 6-TGN/6-MMPR 比值与稳态时的代谢偏斜（第 8 周时 6-MMPR/-6TGN 比值≥11 和≥20）独立相关（均 P <.001）。ADR 的发生和疗效与 T1 时的硫嘌呤代谢产物浓度无独立相关性。
T1 时的硫嘌呤代谢产物浓度与早期治疗停药和稳态时的代谢偏斜相关，但与疗效无关，有助于识别硫嘌呤治疗失败风险较高的患者。
