Department of Medicine, Division of Hematology and Oncology, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, San Francisco, CA, 94143, USA.
Cancer Chemother Pharmacol. 2014 Aug;74(2):359-65. doi: 10.1007/s00280-014-2510-0. Epub 2014 Jun 17.
Inhibition of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is associated with metabolic and immunologic perturbations that impact drug tolerability. Here, we studied whether PI3 kinase/mTOR pathway inhibitors are associated with greater metabolic impact and decreased tolerability in Asian patients.
A retrospective analysis was conducted of consecutive patients with advanced malignancies treated on phase 1 trials of PI3K/mTOR inhibitors. Adverse events related to PI3K/mTOR inhibition, fasting plasma glucose (FPG), insulin, and c-peptide levels, hemoglobin A1c (HgbA1c), and T cell subsets were prospectively collected. Mann-Whitney and Chi-square tests were used to compare continuous and categorical variables, respectively, between Asian and Caucasian patients.
A total of 103 patients (31 Asian; 72 Caucasian) were treated consecutively across five clinical trials. Baseline age, gender distribution, and metabolic parameters were comparable with the exception of lower median body mass index (BMI) in Asian patients (23.0 vs. 24.8 kg/m(2), p = 0.024). There were no differences in drug tolerability, adherence, or duration of therapy. Asian patients experienced a higher incidence of grade ≥ 2 hyperglycemia (37.5 vs. 18.1%, p = 0.03), and greater increases in FPG, HgbA1c, and insulin resistance. No differences in incidence or severity of mucositis, rash, or pneumonitis were observed. Drug effects on neutrophils, lymphocytes, and T cell subsets were similar.
PI3K/mTOR inhibitors have greater glycemic impact in Asian patients, despite similar baseline metabolic parameters, comparable dose intensity, and a lower median BMI. Further studies are warranted to explore the mechanisms underlying these differences and optimize dosing in Asian patients.
磷酸肌醇 3-激酶（PI3K）/哺乳动物雷帕霉素靶蛋白（mTOR）通路的抑制与影响药物耐受性的代谢和免疫改变有关。在此，我们研究了 PI3 激酶/mTOR 通路抑制剂是否与亚洲患者的代谢影响更大和耐受性降低有关。
对接受 PI3K/mTOR 抑制剂的 1 期临床试验的晚期恶性肿瘤连续患者进行回顾性分析。前瞻性收集与 PI3K/mTOR 抑制相关的不良事件、空腹血糖（FPG）、胰岛素和 C 肽水平、糖化血红蛋白（HgbA1c）和 T 细胞亚群。使用 Mann-Whitney 和 Chi-square 检验分别比较亚洲和高加索患者的连续和分类变量。
共对五个临床试验中的 103 例患者（31 例亚洲人；72 例高加索人）进行了连续治疗。除亚洲患者的中位体重指数（BMI）较低（23.0 与 24.8 kg/m2，p = 0.024）外，基线年龄、性别分布和代谢参数无差异。药物耐受性、依从性或治疗持续时间无差异。亚洲患者发生≥2 级高血糖的发生率较高（37.5%与 18.1%，p = 0.03），且 FPG、HgbA1c 和胰岛素抵抗增加更多。未观察到粘膜炎、皮疹或肺炎的发生率或严重程度的差异。药物对中性粒细胞、淋巴细胞和 T 细胞亚群的影响相似。
尽管存在相似的基线代谢参数、相当的剂量强度和中位数 BMI 较低，但 PI3K/mTOR 抑制剂在亚洲患者中具有更大的血糖影响。需要进一步研究以探讨这些差异的机制，并优化亚洲患者的剂量。
