Budde Klemens, Zonnenberg Bernard A, Frost Michael, Cheung Wing, Urva Shweta, Brechenmacher Thomas, Stein Karen, Chen David, Kingswood John Christopher, Bissler John J
Charité Universitätsmedizin, Berlin, Germany.
Universitair Medisch Centrum, Utrecht, The Netherlands.
Br J Clin Pharmacol. 2016 May;81(5):958-70. doi: 10.1111/bcp.12834. Epub 2016 Mar 5.
The purpose was to determine the exposure-response relationship of everolimus in patients with angiomyolipoma from the EXIST-2 trial and to analyze the correlation between exposure and plasma concentrations of angiogenic biomarkers in these patients.
One hundred and eighteen patients with angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM) were randomly assigned 2 : 1 to receive everolimus 10 mg (n = 79) or placebo (n = 39) once daily. Blood samples for determining everolimus concentration were collected at weeks 2, 4, 12, 24 and 48 during double-blind treatment. Plasma samples for biomarker analysis were collected at baseline and weeks 4, 12, 24, 36, 48 and at the end of treatment. Concentrations of eight angiogenic biomarkers associated with tumour growth were determined by enzyme-linked immunosorbent assay (ELISA).
Peak and trough concentrations of everolimus in blood remained stable over time and similar to those reported in other indications. Substantial pharmacodynamic effects were observed in the everolimus, but not placebo, arm for three biomarkers: After 24 weeks of treatment, reduction of vascular endothelial growth factor D (VEGF-D) and collagen type IV (COL-IV) (mean fold-changes with 95% confidence intervals [CI] were 0.36 [0.33, 0.40], and 0.54 [0.51, 0.57], respectively, P < 0.001 for both), along with increased VEGF-A (mean fold-change of 1.59 [1.39, 1.80], P < 0.001), were seen. Furthermore, baseline VEGF-D and COL-IV levels were associated with angiomyolipoma size at baseline and with angiomyolipoma response to everolimus.
These findings suggest that plasma angiogenic markers may provide an objective measure of patient response to everolimus.
本研究旨在通过EXIST - 2试验确定依维莫司在肾血管平滑肌脂肪瘤患者中的暴露 - 反应关系，并分析这些患者中依维莫司暴露量与血管生成生物标志物血浆浓度之间的相关性。
118例与结节性硬化症（TSC）相关的肾血管平滑肌脂肪瘤患者或散发性淋巴管平滑肌瘤病（sLAM）患者按2∶1随机分组，分别每日接受依维莫司10 mg（n = 79）或安慰剂（n = 39）治疗。在双盲治疗期间的第2、4、12、24和48周采集用于测定依维莫司浓度的血样。在基线、第4、12、24、36、48周以及治疗结束时采集用于生物标志物分析的血浆样本。通过酶联免疫吸附测定（ELISA）法测定与肿瘤生长相关的8种血管生成生物标志物的浓度。
依维莫司的血药峰浓度和谷浓度随时间保持稳定，与其他适应症报道的浓度相似。在依维莫司治疗组（而非安慰剂组）中观察到三种生物标志物有显著的药效学效应：治疗24周后，血管内皮生长因子D（VEGF - D）和IV型胶原（COL - IV）降低（平均倍数变化及95%置信区间[CI]分别为0.36[0.33, 0.40]和0.54[0.51, 0.57]，两者P均<0.001），同时VEGF - A升高（平均倍数变化为1.59[1.39, 1.80]，P<0.001）。此外，基线VEGF - D和COL - IV水平与基线时肾血管平滑肌脂肪瘤大小以及肾血管平滑肌脂肪瘤对依维莫司的反应相关。
这些发现表明血浆血管生成标志物可能为患者对依维莫司的反应提供客观指标。
