Prophylaxis of irinotecan-induced diarrhea with neomycin and potential role for UGT1A1*28 genotype screening:: A double-blind, randomized, placebo-controlled study
Prophylaxis of irinotecan-induced diarrhea with neomycin and potential role for UGT1A1*28 genotype screening:: A double-blind, randomized, placebo-controlled study
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DOI：
10.1634/theoncologist.11-8-944
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发表时间：
2006-09-01
期刊：
影响因子：
5.8
通讯作者：
De Jonge, Maja J. A.
中科院分区：
文献类型：
--
作者：
De Jong, Floris A.;Kehrer, Diederik F. S.;De Jonge, Maja J. A.
目标。迟发性腹泻是伊立替康的一种常见副作用，与细菌介导的活性伊立替康代谢物SN-38在肠道中从其葡萄糖醛酸结合物中形成有关。基于一项初步研究，我们假设同时使用抗生素新霉素将减少肠道暴露于SN-38，并改善腹泻的发生率和严重程度。患者接受伊立替康治疗的多中心、双盲、随机、安慰剂对照试验。符合条件的患者接受伊立替康(350 mg/m(2)，每3周一次)联合新霉素(660 mg，每天3次，连续3天，化疗前2天开始)或联合安慰剂治疗。采集血样进行进一步的药代动力学和药物遗传学分析。62例患者可评价为毒性分析。两组患者的基线患者特征、全身SN-38暴露和UGT1AI*28基因状态(即尿苷二磷酸-葡萄糖醛酸基转移酶1A1启动子区的额外TA重复)相似。虽然延迟型腹泻的分布、严重程度和持续时间在两组之间没有显著差异，但新霉素组的3级腹泻倾向于较少发生。至少一个UGT1A1*28等位基因的存在与2-3级腹泻的发生率密切相关。在新霉素组中，2级恶心明显更常见。我们的结果并不表明新霉素在预防伊立替康诱导的迟发性腹泻中起主要作用。提示UGT1A1*28等位基因可作为伊立替康所致迟发性腹泻先天预防的筛查工具。
Objective. Delayed-type diarrhea is a common side effect of irinotecan and is associated with a bacterial-mediated formation of the active irinotecan metabolite SN-38 from its glucuronide conjugate in the intestine. Based on a pilot study, we hypothesized that concomitant administration of the antibiotic neomycin would diminish exposure of the gut to SN-38 and ameliorate the incidence and severity of diarrhea.Patients and Methods. Patients were treated with irinotecan in a multicenter, double-blind, randomized, placebo-controlled trial. Eligible patients received irinotecan (350 mg/m(2) once every 3 weeks) combined with neomycin (660 mg three times daily for three consecutive days, starting 2 days before chemotherapy) or combined with placebo. Blood samples were obtained for additional pharmacokinetic and pharmacogenetic analyses.Results. Sixty-two patients were evaluable for the toxicity analysis. Baseline patient characteristics, systemic SN-38 exposure, and UGT1AI*28 genotype status (i.e., an additional TA repeat in the promoter region of uridine diphosphate-glucuronosyltransferase isoform 1A1) were similar in both arms. Although distribution, severity, and duration of delayed-type diarrhea did not differ significantly between arms, grade 3 diarrhea tended to be less frequent in the neomycin arm. The presence of at least one UGT1A1*28 allele was strongly related to the incidence of grade 2-3 diarrhea. In the neomycin arm, grade 2 nausea was significantly more common.Conclusion. Our results do not suggest a major role for neomycin as prophylaxis for irinotecan-induced delayed-type diarrhea. It is suggested that the UGT1A1*28 genotype status could be used as a screening tool for a priori prevention of irinotecan-induced delayed-type diarrhea.