Thiopurine dose in intermediate and normal metabolizers of thiopurine methyltransferase may differ three-fold
Thiopurine dose in intermediate and normal metabolizers of thiopurine methyltransferase may differ three-fold
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DOI：
10.1016/j.cgh.2008.02.032
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发表时间：
2008-06-01
影响因子：
12.6
通讯作者：
Barclay, Murray L.
中科院分区：
文献类型：
--
作者：
Gardiner, Sharon J.;Gearry, Richard B.;Barclay, Murray L.
背景和目标：炎症性肠病（IBD）患者可能有不同的巯基嘌呤剂量需求与巯基嘌呤甲基转移酶（TPMT）基因型和/或表型。本研究的目的是确定中间与正常TPMT代谢状态下的巯嘌呤剂量需求。方法：对开始使用硫唑嘌呤或6-巯基嘌呤治疗IBD的患者进行9个月的随访。根据6-硫代鸟嘌呤核苷酸（6-TGN）浓度（范围：235-450 pmol/8 x 10（8）个红细胞[RBC]）和临床状态，对巯基嘌呤剂量进行个体化。每三个月进行一次的额外评估包括疾病活动的测量。结果：77名参与者中有8名（10%）因违反方案而退出。其余69例受试者中有52例（75%）（TPMT*1/*1和 *1/*3基因型分别为90%和10%）完成了硫唑嘌呤（n = 46）或6-巯基嘌呤（n = 6）的随访。两种TPMT基因型的平均初始剂量（硫唑嘌呤当量）相似（类似于1 mg/kg/d），但9个月后，TPMT*1/*3组的剂量低50%（0.9 vs 1.8 mg/kg/d，P < .0001）。尽管调整了剂量，但随访期结束时，TPMT*1/*3组的6-TGN浓度中位数仍高出2倍（505 pmol/8 x 10（8）RBC vs 273 pmol/8 x 10（8）RBC，P = .02）。当根据剂量调整浓度时，该差异为3倍（578 pmol/8 x 10（8）/mg/kg/d vs 183 pmol/8 x 10（8），P = .0007）。如果使用TPMT表型而不是基因型，则结果相似。两组间的临床结局无差异。结论：IBD患者达到治疗性6-TGN浓度（>235 pmol/8 × 10（8）RBC）的初始目标剂量可能分别为1 mg/kg/d和3 mg/kg/d。
Background & Aims: Patients with inflammatory bowel disease (IBD) may have different thiopurine dose requirements in relation to thiopurine methyltransferase (TPMT) genotype and/or phenotype. The purpose of this study was to determine thiopurine dose requirements in intermediate versus normal TPMT metabolism status. Methods: Consecutive patients starting azathioprine or 6-mercaptopurine for IBD were followed up for 9 months. The thiopurine dose was individualized using 6-thioguanine nucleotide (6-TGN) concentrations (range, 235-450 pmol/8 x 10(8) red blood cells [RBCs]) and clinical status. Additional assessments undertaken every three months included measures of disease activity. Results: Eight (10%) of 77 participants were withdrawn because of protocol violation. Fifty-two (75%) of the remaining 69 subjects (similar to 90% and 10% with the TPMT*1/*1 and *1/*3 genotypes, respectively) completed follow-up on azathioprine (n = 46) or 6-mercaptopurine (n = 6). The mean initial dose (as azathioprine equivalents) was similar (similar to 1 mg/kg/d) for the 2 TPMT genotypes, but after 9 months the dose was 50% lower in the TPMT*1/*3 group (0.9 vs 1.8 mg/kg/d, P < .0001). Despite dose adjustment, median 6-TGN concentrations still were 2-fold higher in the TPMT*1/*3 group at the end of the follow-up period (505 vs 273 pmol/8 x 10(8) RBCs, P = .02). This difference was 3-fold when the concentration was adjusted for dose (578 vs 183 pmol/8 x 10(8) per mg/kg/d, P = .0007). Results were similar if TPMT phenotype was used instead of genotype. Clinical outcomes did not differ between groups. Conclusions: Initial target doses to attain therapeutic 6-TGN concentrations (>235 pmol/8 x 10(8) RBCs) in patients with IBD might be 1 and 3 mg/kg/d in intermediate and normal metabolizers, respectively.