摘要
目的探讨甲磺酸伊马替尼(IM)及其活性代谢产物N‐去甲基伊马替尼(NDI)稳态血浆谷浓度(谷浓度)对胃肠间质瘤(GIST)患者中重度不良反应发生风险的预测价值及警戒值。方法研究对象选自2020年7月至2021年3月于苏州大学附属第一医院接受IM治疗的GIST门诊复诊患者。对入选患者当即询问并记录其相关临床信息以及入组前28 d内IM相关不良反应发生情况,于复诊当天采血(距上次服药22~24 h)测定IM及NDI谷浓度,并于采血后28 d电话随访IM相关不良反应发生情况;通过医院信息系统收集患者采血前、后各28 d内血常规和血生化检查结果。对不良反应进行因果关系判断和严重程度分级后,以未发生和发生Ⅰ级不良反应者为无/轻度组,发生Ⅱ~Ⅴ级不良反应者为中重度组,通过2组患者主要临床特征的比较分析发生中重度不良反应的危险因素,采用受试者工作特征(ROC)曲线分析IM及NDI谷浓度对中重度不良反应发生风险的预测价值及警戒值。结果纳入分析的患者共119例,113例(95.0%)发生不良反应,无/轻度组65例,中重度组54例。2组患者性别分布和给药剂量分布的差异有统计学意义(χ²=19.772,P<0.001;χ²=9.817,P=0.020),中重度组女性患者占比、给药剂量为300 mg/d者占比和给药剂量为600 mg/d者占比均高于无/轻度组。中重度组患者IM和NDI谷浓度均明显高于无/轻度组,差异均有统计学意义[1695(1258,2261)μg/L比1360(938,1643)μg/L,P<0.001;324(223,379)μg/L比264(217,338)μg/L,P=0.042]。ROC曲线分析结果显示,GIST患者发生中重度不良反应的IM和NDI谷浓度折点分别为1539μg/L(敏感度62.3%,特异度70.3%)和303μg/L(敏感度56.6%,特异度68.7%),以折点浓度将119例患者分组,中重度不良反应发生率IM谷浓度>1539μg/L组和≤1539μg/L组分别为63.0%(34/54)和30.8%(20/65),NDI谷浓度>303μg/L组和≤303μg/L组分别为59.6%(31/52)和34.3%(23/67),差异均有统计学意义(P<0.001;P=0.006)。结论IM和NDI谷浓度对GIST患者中重度不良反应发生风险有一定预测价值。对IM谷浓度>1539μg/L和NDI谷浓度>303μg/L的患者应加强用药监测,以保证用药安全。
Objective To explore the value and threshold of steady‐state trough plasma concen‐tration(trough concentration)of imatinib mesylate(IM)and its active metabolite N‐desmethyl imatinib(NDI)in predicting the risk of moderate to severe adverse reactions in patients with gastrointestinal stromal tumors(GIST).Methods The subjects were selected from GIST outpatient who received IM treatment and re‐visited doctor in the First Affiliated Hospital of Soochow University form July 2020 to March 2021.On the day of re‐visiting,the relevant clinical information and occurrence of IM‐related adverse reactions within 28 d prior to the trial of selected patients was asked and recorded and blood were collected(22 to 24 hours after the last medication)to determine IM and NDI trough concentration.Twenty‐eight days after blood collection,tele‐phone follow‐up was conducted to record IM‐related adverse reactions occurrence.Blood routine and blood biochemical examination results within 28 days before and after blood collection were collected through the hospital information system.After evaluating causality for adverse reactions and grading their severity,patients without or with grade I adverse reactions were regarded asthe no/mild group andthose with gradeⅡ~Ⅴadverse reactions were regarded as the moderate‐severe group.The risk factors of moderate‐severe adverse reactions were analyzed by comparing the main clinical characteristics of patients in the 2 groups,and the value and threshold of IM and NDI trough concentrations in predicting the risk of moderate‐severe adverse reactions were analyzed by receiver operating characteristic(ROC)curve.Results A total of 119 patients were recruited in this study and 113(95.0%)had adverse reactions.There were 65 patients in the no/mild group and 54 in the moderate‐severe group.The differences in the gender and dose distribution of patients in the 2 groups were statistically significant(χ²=19.772,P<0.001;χ²=9.817,P=0.020);proportions of females,patients at dose of 300 mg/d,and patients at dose of 600 mg/d in the moderate‐severe group were greater than those in the no/mild group.The trough concentration of IM and NDI of patients in the moderate‐severe group were significantly higher than those of patients in the no/mild group[1695(1258,2261)μg/L vs.1360(938,1643)μg/L,P<0.001;324(223,379)μg/L vs.264(217,338)μg/L,P=0.042].ROC curve analysis results showed that the breakpoints of IM and NDI trough concentrations for moderate‐severe adverse reactions in patients with GIST were 1539μg/L(sensitivity 62.3%,specificity 70.3%)and 303μg/L(sensitivity 56.6%,specificity 68.7%)respectively.The 119 patients were grouped according to the break‐point concentrations.The incidences of moderate‐severe adverse reactions were 63.0%(34/54)and 30.8%(20/65)in patients with IM trough concentration>1539μg/L and≤1539μg/L,respectively and 59.6%(31/52)and 34.3%(23/67)in patients with NDI trough concentration>303μg/L and≤303μg/L,respec‐tively.The differences were statistically significant(P<0.001,P=0.006).Conclusions The trough concen‐trations of IM and NDI are of some value in predicting the risk of moderate‐severe adverse reactions in patients with GIST.Drug monitoring should be strengthened in patients with IM trough concentration>1539μg/L and NDI trough concentration>303μg/L to ensure the safety of IM use.
作者
张梦华
陈之遥
刘筱雪
单治理
杨刚
周启阳
周雨迪
周晓俊
缪丽燕
Zhang Menghua;Chen Zhiyao;Liu Xiaoxue;Shan Zhili;Yang Gang;Zhou Qiyang;Zhou Yudi;Zhou Xiaojun;Miao Liyan(Department of Clinical Pharmacology Research Laboratory,First Affiliated Hospital of Soochow University,Jiangsu Province,Suzhou 215006,China;Department of Pharmacology,First Affiliated Hospital of Soochow University,Jiangsu Province,Suzhou 215006,China;Department of General Surgery,First Affiliated Hospital of Soochow University,Jiangsu Province,Suzhou 215006,China)
出处
《药物不良反应杂志》
CSCD
2021年第10期517-522,共6页
Adverse Drug Reactions Journal
基金
苏州市科技局民生科技项目‐医疗卫生应用基础研究(SYS2018039)
江苏省研究型医院学会精益化用药科研基金(JY202007)。
