卡博替尼与卡巴他赛序贯治疗去势抵抗性前列腺癌的药物动力学与药效动力学研究

There have been more drugs approved by the US Food and Drug Administration for the treatment of castration-resistant prostate cancer (CRPC) in the past 3 years than in the prior 3 decades, with additional drugs on the verge of approval based on the results of recently reported randomized trials. With the development of multiple new agents with diverse mechanisms of action for the treatment of CRPC, the optimal sequencing of drugs for clinical use becomes a major unanswered question. The aim of our study is to 1) investigate the pharmacological effects of different cabozantinib and cabazitaxel combination schedules by in vitro and in vivo experiments and 2) to develop a Pharmacokinetic/Pharmacodynamic (PK/PD) model characterizing and quantifying the anti-cancer effect of combination therapies using time-dependent data. Based on the promising outcomes fo our recent priliminary study on ' Preclinical PK/PD Models to Predict Schedule-Dependent Interaction Between Erlotinib and Gemcitabine.', our future research will focus on 1) in vitro studies with seven different cabozantinib combined with cabazitaxel schedules. Cell growth inhibition, protein modulation in relative signaling pathway, and cell cycle distribution will be analyzed to evaluate the pharmacological effects of different schedules, and combination index will be calculated to assess the interaction between two drugs. 2) a preclinical in vivo study to compare the tumor inhibition and toxicity between cabozantinib monotherapy, cabazitaxel monotherapy, cabozantinib and cabazitaxel used simultaneously, cabozantinib and cabazitaxel used with interval in LAPC-4 cells xenograft tumor model in male BALB/c nude mice. 3) development of a mechanism-based PK/PD model to quantitatively describe the relationships between plasma concentration of cabozantinib and/or cabazitaxel, serum prostate specific antigen (PSA) and tumor inhibition. This mechanism-based PK/PD modeling we build can explicitly distinguish between drug-specific and biological system-specific parameters. Drug-specific parameters describe the interaction between the drug and the biological system in terms of target affinity and target activation, whereas system-specific parameters describe the functioning of tumor growth. The mechanism-based PK/PD model together with CRPC patient-level system-specific parameters can be used to simulate and predict the schedule-dependent interaction between cabozantinib and cabazitaxel in clinic. It is our expectation that the results from conducting the proposed research projects could contribute greatly to 1) the discovery of new drug candidates of CRPC with our predictable PK/PD model and 2) optimize the sequencing of cabozantinib and cabazitaxel combination therapy for clinical use.

去势抵抗性前列腺癌(CRPC)是威胁男性健康最常见的恶性肿瘤之一。近年来多个临床新药的获批为CRPC患者带来福音的同时也产生了临床用药选择和联合用药方式的困惑。靶向药物卡博替尼和化疗新药卡巴他赛联合治疗CRPC的增益研究尚属空白。通过文献调研和前期工作提出假设：序贯治疗能够优化卡博替尼和卡巴他赛联合治疗CRPC的疗效；通过基于前列腺特异性抗体(PSA)肿瘤标志物机制的PK/PD模型可模拟预测临床上两种新药序贯治疗CRPC的疗效。本研究拟在细胞水平采用SRB和流式细胞术考察两种新药单独用药、联合同时给药和序贯给药对肿瘤生长的抑制作用。在荷瘤鼠模型中评价其药动学和药效学性质，并建立基于机制的PK/PD模型描述血药浓度、PSA水平和肿瘤抑制的定量关系，用以模拟预测卡博替尼和卡巴他赛在CRPC患者中序贯治疗的增益。课题将对CRPC新药开发和用药选择提供新思路和建议，具有广阔应用前景和重要临床意义。

多个临床新药的获批为去势抵抗性前列腺癌(CRPC)的临床用药选择和联合用药方式提出了新的挑战。本项目旨在CRPC肿瘤细胞水平定性地、以及在荷瘤裸鼠模型中采用药物动力学/药效动力学(PK/PD)模型定量研究靶向药物卡博替尼和化疗药物多西他赛单独给药、联合给药和序贯给药对CRPC肿瘤细胞生长的抑制作用，以此模拟预测卡博替尼和卡巴他赛在临床CRPC 患者中联合治疗的增益。. 体外药效学研究表明，卡博替尼和多西他赛单药给药对PC-3、DU145和22Rv1 三种CRPC细胞系的体外增殖均有明显的抑制效果；两药联合给药和序贯给药对该三种CRPC细胞系的体外增殖的抑制效果均比两药单药使用强，但抑制效应的协同指数随着给药浓度的增加而增大，表明联合给药和序贯给药均存在明显的拮抗作用。. 采用液质联用技术分别建立了灵敏、简便、快速、稳定的卡博替尼和多西他赛的动物体内分析方法。这两种分析方法在卡博替尼 0.5-1000 ng/mL和卡巴他赛5-1500ng/mL范围内线性关系良好，方法的专属性、准确度、精密度、稳定性、稀释效应等均满足药物在荷瘤裸鼠中血药浓度的测定。荷瘤裸鼠100 mg/kg卡博替尼灌胃给药后，其药物动力学符合零级吸收二室分布模型。卡博替尼血浆清除率为0.371 L/kg/h。荷瘤裸鼠20 mg/kg卡巴他赛尾静脉给药后，其药物动力学符合二室分布模型。荷瘤裸鼠血浆清除率为3.04 L/kg/h。..荷瘤裸鼠体内药效学研究表明，不同组合的卡博替尼和多西他赛序贯给药方案比两药单独给药的肿瘤生长抑制效果强，弱于多西他赛和卡博替尼同时联合给药组。但卡博替尼和多西他赛序贯给药方案在安全性上体现了一定的优势。本研究建立的PK/PD模型能准确描述荷瘤裸鼠中CRPC肿瘤自然生长过程，以及卡博替尼和多西他赛单独给药、联合给药和序贯给药后肿瘤体积随时间的变化过程。所建立的PK/PD模型用于模拟预测卡博替尼和卡巴他赛在CRPC患者中联合治疗的增益。.本项目的研究对CRPC 临床用药的选择提供新思路和建议，具有重要的临床意义。同时所建立PK/PD 模型可用于预测其他同类型药物治疗CRPC 的疗效，对新药的开发具有广阔的应用前景和实用价值。