Randomised clinical trial: individualised vs. weight-based dosing of azathioprine in Crohn's disease.
Randomised clinical trial: individualised vs. weight-based dosing of azathioprine in Crohn's disease.
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DOI：
10.1111/apt.12555
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发表时间：
2014-01
影响因子：
7.6
通讯作者：
Hanauer SB
中科院分区：
文献类型：
--
作者：
Dassopoulos T;Dubinsky MC;Bentsen JL;Martin CF;Galanko JA;Seidman EG;Sandler RS;Hanauer SB
硫唑嘌呤（Azathioprine，AZA）是一种前体药物，可代谢为6-硫代鸟嘌呤核苷酸（6-thioguanine nucleotides，6 TGN），是治疗克罗恩病（Crohn's disease，CD）的一种激素保留疗法。该试验研究了基于巯嘌呤甲基转移酶（TPMT）活性和6 TGN浓度的AZA治疗是否通过个体化给药进行优化。这项多中心、双盲、随机对照试验比较了基于体重与个体化AZA给药在诱导和维持类固醇治疗CD成人和儿童缓解方面的疗效和安全性。主要结局是16周时的临床缓解（CR）。在基于体重的组中，受试者接受2.5 mg/kg/d。在个体化给药组中，初始AZA剂量为1.0 mg/kg/d（如果TPMT中等）或2.5 mg/kg/d（如果TPMT正常）。从第5周开始，将剂量调整至目标6 TGN浓度250-400 pmol/8x 108红细胞（RBC），或调整至最大剂量4 mg/kg/d。在随机分配50例受试者后，由于入组人数不足，试验提前停止。在意向治疗分析中，个体化组第16周的CR率为40%，基于体重组为16%（p=0.11）。在符合方案（PP）分析中，个体化组第16周CR率为60%，基于体重组为25%（p=0.12）。第16周时，PP缓解者和非缓解者的中位6 TGN浓度分别为216和149 pmol/8x 108 RBC（p=0.07）。尽管倾向于个体化AZA给药优于基于体重的AZA给药，但疗效无统计学显著性差异，可能是由于统计学把握度较低，且个体化组无法达到目标6 TGN浓度。
Azathioprine (AZA), a pro-drug metabolized to the active metabolites 6-thioguanine nucleotides (6TGN), is a steroid-sparing therapy for Crohn’s disease (CD). This trial investigated whether AZA therapy is optimized by individualized dosing based on thiopurine methyltransferase (TPMT) activity and 6TGN concentrations. This multicenter, double-blind, randomized controlled trial compared the efficacy and safety of weight-based vs. individualized AZA dosing in inducing and maintaining remission in adults and children with steroid-treated CD. The primary outcome was clinical remission (CR) at 16 weeks. In the weight-based arm, subjects received 2.5 mg/kg/d. In the individualized dosing arm, the initial AZA dose was 1.0 mg/kg/d (if intermediate TPMT) or 2.5 mg/kg/d (if normal TPMT). Starting at week 5, the dose was adjusted to target 6TGN concentrations of 250–400 pmol/8x108 red blood cells (RBC), or to a maximal dose of 4 mg/kg/d. After randomizing 50 subjects, the trial was stopped prematurely due to insufficient enrollment. In intention-to-treat analysis, CR rates at week 16 were 40% in the individualized arm vs. 16% in the weight-based arm (p=0.11). In per-protocol (PP) analysis, week 16 CR rates were 60% in the individualized arm and 25% in the weight-based arm (p=0.12). At week 16, median 6TGN concentrations in PP remitters and non-remitters were 216 and 149 pmol/8x108 RBC respectively (p=0.07). Despite trends favoring individualized over weight-based AZA dosing, there were no statistically significant differences in efficacy, likely due to low statistical power and inability to achieve the target 6TGN concentrations in the individualized arm.
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