Pharmacokinetic-Pharmacodynamic Modeling of Tumor Growth Inhibition and Biomarker Modulation by the Novel Phosphatidylinositol 3-Kinase Inhibitor GDC-0941
Pharmacokinetic-Pharmacodynamic Modeling of Tumor Growth Inhibition and Biomarker Modulation by the Novel Phosphatidylinositol 3-Kinase Inhibitor GDC-0941
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DOI：
10.1124/dmd.110.032912
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发表时间：
2010-09-01
影响因子：
3.9
通讯作者：
Wallin, Jeffrey J.
中科院分区：
文献类型：
--
作者：
Salphati, Laurent;Wong, Harvey;Wallin, Jeffrey J.
磷脂酰肌醇3-激酶（PI 3 K）途径是细胞周期和增殖的主要决定因素。通过p110 α亚基的激活或转化突变，其失调与许多癌症的发展有关。2-（1H-吲唑-4-基）-6-（4-甲磺酰基-哌嗪-1-基甲基）-4-吗啉-4-基-噻吩并[3，2-d]嘧啶（GDC-0941）是一种新型的PI 3 K小分子抑制剂，目前正在临床上作为抗癌剂进行评估。这些研究的目的是表征MCF 7.1乳腺癌异种移植物中GDC-0941血浆浓度与肿瘤缩小之间的关系，并评价肿瘤药效学生物标志物[磷酸化（p）Akt和磷酸化富含脯氨酸的40 kDa Akt底物（pPRAS 40）]反应与抗肿瘤疗效之间的相关性。用GDC-0941以各种剂量（12.5-200 mg/kg）和给药时间表（每日至每周）治疗携带MCF 7.1肿瘤的小鼠长达3周。与肿瘤生长数据拟合的间接反应模型表明，肿瘤停滞所需的GDC-0941血浆浓度约为0.3 μ M。在12.5、50或150 mg/kg的单次口服剂量后，还研究了GDC-0941血浆浓度与肿瘤中pAkt和pPRAS 40的抑制之间的关系。间接反应模型拟合Akt和PRAS 40磷酸化数据的抑制，并提供pAkt和pPRAS 40的IC（50）估计值分别为0.36和0.29 μ M。使用整合的药代动力学生物标志物肿瘤生长模型进一步探索pAkt抑制与肿瘤体积之间的关系，该模型显示在MCF 7.1异种移植物的GDC-0941处理后需要至少30%的pAkt抑制以实现停滞。
The phosphatidylinositol 3-kinase (PI3K) pathway is a major determinant of cell cycling and proliferation. Its deregulation, by activation or transforming mutations of the p110 alpha subunit, is associated with the development of many cancers. 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) is a novel small molecule inhibitor of PI3K currently being evaluated in the clinic as an anticancer agent. The objectives of these studies were to characterize the relationships between GDC-0941 plasma concentrations and tumor reduction in MCF7.1 breast cancer xenografts and to evaluate the association between the tumor pharmacodynamic biomarker [phosphorylated (p) Akt and phosphorylated pro-line-rich Akt substrate of 40 kDa (pPRAS40)] responses and antitumor efficacy. MCF7.1 tumor-bearing mice were treated for up to 3 weeks with GDC-0941 at various doses (12.5-200 mg/kg) and dosing schedules (daily to weekly). An indirect response model fitted to tumor growth data indicated that the GDC-0941 plasma concentration required for tumor stasis was approximately 0.3 mu M. The relationship between GDC-0941 plasma concentrations and inhibition of pAkt and pPRAS40 in tumor was also investigated after a single oral dose of 12.5, 50, or 150 mg/kg. An indirect response model was fitted to the inhibition of Akt and PRAS40 phosphorylation data and provided IC(50) estimates of 0.36 and 0.29 mu M for pAkt and pPRAS40, respectively. The relationship between pAkt inhibition and tumor volume was further explored using an integrated pharmacokinetic biomarker tumor growth model, which showed that a pAkt inhibition of at least 30% was required to achieve stasis after GDC-0941 treatment of the MCF7.1 xenograft.