Vázquez Carolina, Orlova María, Verzura María Alicia, Minatta José Nicolás, Scibona Paula, Jáuregui Esteban Gabriel, Díaz de Arce Heidy, Pallotta María Guadalupe, Belloso Waldo Horacio
a Clinical Pharmacology Section, Internal Medicine Department , Hospital Italiano de Buenos Aires, Buenos Aires , Argentina.
b Internal Medicine Department , Hospital Italiano de Buenos Aires , Buenos Aires , Argentina.
J Chemother. 2019 Apr;31(2):95-104. doi: 10.1080/1120009X.2019.1572287. Epub 2019 Feb 10.
Pemetrexed is an antimetabolite approved for treatment of non-small cell lung cancer. Harbouring interindividual variability in both the pharmacokinetic and pharmacogenetic profiles may lead to life-threatening toxicities. A prospective cohort study of adult patients initiating treatment with pemetrexed in combination with platinum between 2013 and 2015 were follow up. Primary exposure were the methylenetetrahydrofolate reductase (MTHFR) single base polymorphisms in exon 4 and 7 and 5'-UTR- thymidylate synthase (TYMS) VNTR genotypes, in addition to baseline clinical and demographic variables. We used a Cox regression model to evaluate patient's survival and toxicity experience and its association with both baseline characteristics, and a-priori determined genetic polymorphisms. Seventy two patients were included, 52.7% developed severe hematologic toxicity during follow-up. None of the tested genotypes were significantly associated with the main outcome on multivariate analysis, nor other basal clinical variables. Overall survival between patients experiencing the outcome was not different from those without it, but hospital admissions were more frequent. MTHFR and 5'-UTR-TYMS genotypes were not useful for predicting high grade toxicity events in patients under treatment with pemetrexed.
培美曲塞是一种被批准用于治疗非小细胞肺癌的抗代谢药物。药代动力学和药物遗传学特征存在个体间差异可能会导致危及生命的毒性反应。对2013年至2015年间开始接受培美曲塞联合铂类治疗的成年患者进行了一项前瞻性队列研究并进行随访。主要暴露因素除了基线临床和人口统计学变量外，还包括亚甲基四氢叶酸还原酶（MTHFR）第4和7外显子的单碱基多态性以及5'-非翻译区-胸苷酸合成酶（TYMS）可变数目串联重复序列（VNTR）基因型。我们使用Cox回归模型来评估患者的生存情况和毒性经历及其与基线特征以及预先确定的基因多态性之间的关联。纳入了72例患者，52.7%的患者在随访期间发生了严重血液学毒性。在多变量分析中，所检测的基因型均与主要结局无显著关联，其他基础临床变量也无关联。发生该结局的患者与未发生该结局的患者总体生存率无差异，但住院次数更多。MTHFR和5'-UTR-TYMS基因型对于预测接受培美曲塞治疗患者的高级别毒性事件并无帮助。
