Takasaki Shinya, Yamaguchi Hiroaki, Kawasaki Yoshihide, Kikuchi Masafumi, Tanaka Masaki, Ito Akihiro, Mano Nariyasu
1Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8574 Japan.
2Department of Urology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, Miyagi 980-8574 Japan.
J Pharm Health Care Sci. 2019 Mar 12;5:6. doi: 10.1186/s40780-019-0135-5. eCollection 2019.
Everolimus is an oral inhibitor of mammalian target of rapamycin, approved for metastatic renal cell carcinoma (mRCC). Recently, personalized medicine through therapeutic drug monitoring (TDM) is recommended in cancer therapy. In this study, the relationship between everolimus blood concentration and clinical outcomes on a long-term were evaluated in Japanese patients with mRCC.
Patients with mRCC were enrolled following treatment with everolimus at Tohoku University Hospital between April 2012 and December 2016. The relationship between everolimus trough blood concentration on day 8 of everolimus therapy and just before discontinuation or dose reduction, and their adverse events were evaluated. Patients were divided into two groups based on the median of everolimus blood concentration on day 8 of treatment, and the profiles of adverse events, and efficacy [time to treatment failure (TTF) and progression-free survival (PFS)] were evaluated.
The median (range) everolimus blood concentrations on day 8 after starting everolimus administration and just before discontinuation or dose reduction were 15.3 (8.1-28.0) ng/mL and 14.8 (6.4-58.4) ng/mL, respectively, with no significant difference between these values ( = 0.3594). Patients ( = 6) with discontinuation or dose reduction following adverse events in everolimus therapy had significantly higher blood concentrations than patients ( = 4) with dose maintenance on both day 8 (median, 18.0 vs 8.2 ng/mL; = 0.0139) and just before discontinuation or dose reduction (median, 22.9 vs 9.7 ng/mL; = 0.0142). Median TTF and PFS of the total patients ( = 10) were 96 days (95% confidence interval [CI], 26-288) and 235 days (95% CI, 28-291), respectively. Subgroup analysis showed that TTF of the patients with > 15.3 ng/mL ( = 5) was not significantly different from that of the patients with ≤15.3 ng/mL ( = 5; = 0.5622). Similarly, PFS of the patients with > 15.3 ng/mL was not significantly different from that of the patients with ≤15.3 ng/mL ( = 0.3436).
This study demonstrated the long-term relationship between everolimus blood level and clinical outcomes and adverse events in Japanese patients with mRCC. Thus, TDM in everolimus therapy could be a useful tool for the early prediction of adverse events for Japanese patients with mRCC.
依维莫司是一种口服哺乳动物雷帕霉素靶蛋白抑制剂，已被批准用于治疗转移性肾细胞癌（mRCC）。近来，癌症治疗中推荐通过治疗药物监测（TDM）实现个性化医疗。本研究评估了日本mRCC患者依维莫司血药浓度与长期临床结局之间的关系。
2012年4月至2016年12月期间，在东北大学医院接受依维莫司治疗的mRCC患者被纳入研究。评估依维莫司治疗第8天和即将停药或减药前的依维莫司谷血药浓度及其不良事件之间的关系。根据治疗第8天依维莫司血药浓度的中位数将患者分为两组，评估不良事件和疗效[治疗失败时间（TTF）和无进展生存期（PFS）]。
开始依维莫司给药后第8天和即将停药或减药前，依维莫司血药浓度的中位数（范围）分别为15.3（8.1 - 28.0）ng/mL和14.8（6.4 - 58.4）ng/mL，这些值之间无显著差异（P = 0.3594）。依维莫司治疗中因不良事件停药或减药的患者（n = 6）在第8天（中位数，18.0 vs 8.2 ng/mL；P = 0.0139）和即将停药或减药前（中位数，22.9 vs 9.7 ng/mL；P = 0.0142）的血药浓度均显著高于维持剂量的患者（n = 4）。全部患者（n = 10）的中位TTF和PFS分别为96天（95%置信区间[CI]，26 - 288）和235天（95%CI，28 - 291）。亚组分析显示，血药浓度>15.3 ng/mL的患者（n = 5）的TTF与血药浓度≤15.3 ng/mL的患者（n = 5）的TTF无显著差异（P = 0.5622）。同样，血药浓度>15.3 ng/mL的患者的PFS与血药浓度≤15.3 ng/mL的患者的PFS无显著差异（P = 0.3436）。
本研究证明了日本mRCC患者依维莫司血药水平与临床结局及不良事件之间的长期关系。因此，依维莫司治疗中的TDM可能是早期预测日本mRCC患者不良事件的有用工具。
