Singh Aman P, Guo Leiming, Verma Ashwni, Wong Gloria Gao-Li, Shah Dhaval K
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Kapoor Hall, Buffalo, New York, NY 14214-8033, USA.
Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, New York, NY 14214-8033, USA.
Pharmaceutics. 2019 Feb 25;11(2):98. doi: 10.3390/pharmaceutics11020098.
Here, we have presented the development of a systems pharmacokinetics-pharmacodynamics (PK-PD) model for antibody-drug conjugates (ADCs), which uses intracellular target occupancy to drive in-vivo efficacy. The model is built based on PK and efficacy data generated using Trastuzumab-Valine-Citrulline-Monomethyl Auristatin E (T-vc-MMAE) ADC in N87 (high-HER2) and GFP-MCF7 (low-HER2) tumor bearing mice. It was observed that plasma PK of all ADC analytes was similar between the two tumor models; however, total trastuzumab, unconjugated MMAE, and total MMAE exposures were >10-fold, ~1.6-fold, and ~1.8-fold higher in N87 tumors. In addition, a prolonged retention of MMAE was observed within the tumors of both the mouse models, suggesting intracellular binding of MMAE to tubulin. A systems PK model, developed by integrating single-cell PK model with tumor distribution model, was able to capture all in vivo PK data reasonably well. Intracellular occupancy of tubulin predicted by the PK model was used to drive the efficacy of ADC using a novel PK-PD model. It was found that the same set of PD parameters was able to capture MMAE induced killing of GFP-MCF7 and N87 cells in vivo. These observations highlight the benefit of adopting a systems approach for ADC and provide a robust and predictive framework for successful clinical translation of ADCs.
在此，我们展示了一种用于抗体药物偶联物（ADC）的系统药代动力学-药效学（PK-PD）模型的开发，该模型利用细胞内靶点占有率来驱动体内疗效。该模型基于使用曲妥珠单抗-缬氨酸-瓜氨酸-单甲基奥瑞他汀E（T-vc-MMAE）ADC在荷N87（高HER2）和GFP-MCF7（低HER2）肿瘤小鼠中产生的PK和疗效数据构建。观察到两种肿瘤模型中所有ADC分析物的血浆PK相似；然而，N87肿瘤中总曲妥珠单抗、未偶联的MMAE和总MMAE暴露量分别高>10倍、1.6倍和1.8倍。此外，在两种小鼠模型的肿瘤中均观察到MMAE的保留时间延长，表明MMAE在细胞内与微管蛋白结合。通过将单细胞PK模型与肿瘤分布模型整合开发的系统PK模型能够较好地合理捕捉所有体内PK数据。PK模型预测的微管蛋白细胞内占有率被用于使用新型PK-PD模型驱动ADC的疗效。发现同一组PD参数能够捕捉MMAE在体内诱导的GFP-MCF7和N87细胞杀伤。这些观察结果突出了采用系统方法研究ADC的益处，并为ADC的成功临床转化提供了一个强大且可预测的框架。
