背景:手足皮肤反应(HFSR)是多激酶抑制剂(MKI)的常见剂量限制性不良反应,其机制尚未完全了解,预防是不够的。
目的:在本试验研究中,双盲,我们进行了随机安慰剂对照试验,以评估局部尿素在肾细胞癌患者舒尼替尼诱导的HFSR二级预防中的作用.
方法:在55名筛查患者中,14人随机接受局部尿素或安慰剂4周。HFSR与舒尼替尼及其代谢物(正去乙基舒尼替尼)的药物水平的关联,VEGFR2基因的遗传多态性,还评估了生活质量(QOL)和生化指标.
结果:结果表明,基于尿素的乳膏并不优于安慰剂(P=.075)。两组的QOL均无变化。检查了位于4号染色体VEGFR2基因中的两个核苷酸rs1870377和rs2305948的单核苷酸多态性。与野生型相比,rs1870377的SNP(变体T>A)与新HFSR的出现有关,尽管相关性无统计学意义(OR0.714).与安慰剂组相比,尿素组中舒尼替尼和N-去乙基舒尼替尼的平均血浆水平之间没有统计学上的显著差异。舒尼替尼的最佳群体药代动力学模型是具有一阶吸收和线性消除的单室模型。根据Ka的群体药代动力学模型计算的群体参数的中位数(IQR),V和Cl为0.22(0.21-0.24)h-1,4.4(4.09-4.47)L,0.049(0.042-0.12)L/hr,分别。
结论:研究表明,在接受舒尼替尼4:2方案的肾癌患者中,尿素乳膏在减少新的HFSR出现方面并不优于安慰剂。
BACKGROUND: Hand foot skin reaction (HFSR) is a common dose-limiting adverse effect of multi kinase inhibitors (MKI) whose mechanism is not fully understood, and the prophylaxis is inadequate.
OBJECTIVE: In this pilot
study, a double-blind, randomized placebo-controlled
trial was conducted to evaluate the effect of topical urea in secondary prevention of sunitinib-induced HFSR in renal cell cancer patients.
METHODS: Out of 55 screened patients, 14 were randomized to receive topical urea or placebo for four weeks. The association of HFSR with drug levels of sunitinib and its metabolite (n-desethyl sunitinib), genetic polymorphism of VEGFR2 gene, quality of life (QOL) and biochemical markers was also assessed.
RESULTS: The results showed that urea-based cream was not superior to placebo (P = .075). There was no change in the QOL in both the groups. Single nucleotide polymorphism was checked for two nucleotides rs1870377 and rs2305948 located in VEGFR2 gene on chromosome 4. SNP (variant T > A) at rs1870377 was associated with appearance of new HFSR as compared to the wild type, although the association was not statistically significant (OR 0.714). There was no statistically significant difference between mean plasma levels of sunitinib and N-desethyl sunitinib in urea arm as compared to placebo arm as compared to placebo. The best fit population pharmacokinetic model for sunitinib was one compartment model with first order absorption and linear elimination. The median (IQR) of population parameters calculated from the population pharmacokinetics model for Ka, V and Cl was 0.22 (0.21-0.24) h-1, 4.4 (4.09-4.47) L, 0.049 (0.042-0.12) L/hr, respectively.
CONCLUSIONS: The
study suggested that the urea-based cream was not superior to placebo in decreasing the appearance of new HFSR in renal cancer patients receiving 4:2 regimen of sunitinib.