Li Jing-Yun, Ren Yu-Peng, Yuan Yin, Ji Shuang-Min, Zhou Shu-Pei, Wang Li-Jie, Mou Zhen-Zhen, Li Liang, Lu Wei, Zhou Tian-Yan
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Department of Laboratory Animal Science, Health Science Center, Peking University, Beijing 100191, China.
Acta Pharmacol Sin. 2016 Jul;37(7):930-40. doi: 10.1038/aps.2016.55. Epub 2016 May 16.
Combined therapy of EGFR TKI and VEGFR TKI may produce a greater therapeutic benefit and overcome EGFR TKI-induced resistance. However, a previous study shows that a combination of EGFR TKI erlotinib (ER) with VEGFR TKI sunitinib (SU) did not improve the overall survival in patients with non-small-cell lung cancer (NSCLC). In this study we examined the anticancer effect of ER, SU and their combination in the treatment of A549 human NSCLC xenograft mice, and conducted PK/PD modeling and simulations to optimize the dose regimen.
ER (20, 50 mg·kg(-1)·d(-1)) or SU (5, 10, 20 mg·kg(-1)·d(-1)) alone, or their combination were administered to BALB/c nude mice bearing A549 tumors for 22 days. The tumor size and body weight were recorded daily. The experimental data were used to develop PK/PD models describing the quantitative relationship between the plasma concentrations and tumor suppression in different dose regimens. The models were further evaluated and validated, and used to predict the efficacy of different combination regimens and to select the optimal regimen.
The in vivo anticancer efficacy of the combination groups was much stronger than that of either drug administered alone. A PK/PD model was developed with a combination index (φ) of 4.4, revealing a strong synergistic effect between ER and SU. The model simulation predicted the tumor growth in different dosage regimens, and showed that the dose of SU played a decisive role in the combination treatment, and suggested that a lower dose of ER (≤5 mg·kg(-1)·d(-1)) and adjusting the dose of SU might yield a better dosage regimen for clinical research.
The experimental data and modeling confirm synergistic anticancer effect of ER and SU in the treatment of A549 xenograft mice. The optimal dosage regimen determined by the PK/PD modeling and simulation can be used in future preclinical study and provide a reference for clinical application.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR TKI）与血管内皮生长因子受体酪氨酸激酶抑制剂（VEGFR TKI）联合治疗可能产生更大的治疗效益并克服EGFR TKI诱导的耐药性。然而，先前一项研究表明，EGFR TKI厄洛替尼（ER）与VEGFR TKI舒尼替尼（SU）联合使用并不能提高非小细胞肺癌（NSCLC）患者的总生存期。在本研究中，我们检测了ER、SU及其联合用药对A549人NSCLC异种移植小鼠的抗癌效果，并进行药代动力学/药效学（PK/PD）建模与模拟以优化给药方案。
将单独使用ER（20、50 mg·kg⁻¹·d⁻¹）或SU（5、10、20 mg·kg⁻¹·d⁻¹），或二者联合用药给予荷A549肿瘤的BALB/c裸鼠，给药22天。每天记录肿瘤大小和体重。利用实验数据建立PK/PD模型，描述不同给药方案下血浆浓度与肿瘤抑制之间的定量关系。对模型进行进一步评估和验证，并用于预测不同联合方案的疗效及选择最佳方案。
联合用药组的体内抗癌效果比单独使用任一药物都要强得多。建立了一个联合指数（φ）为4.4的PK/PD模型，揭示了ER与SU之间有很强的协同效应。模型模拟预测了不同给药方案下的肿瘤生长情况，表明SU的剂量在联合治疗中起决定性作用，并提示较低剂量的ER（≤5 mg·kg⁻¹·d⁻¹）并调整SU的剂量可能为临床研究产生更好的给药方案。
实验数据和建模证实了ER与SU联合治疗A549异种移植小鼠具有协同抗癌效果。通过PK/PD建模与模拟确定的最佳给药方案可用于未来的临床前研究，并为临床应用提供参考。
