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Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice
Pharmaceutics ( IF 5.4 ) Pub Date : 2020-10-15 , DOI: 10.3390/pharmaceutics12100975
Javier Reig-López , María del Mar Maldonado , Matilde Merino-Sanjuan , Ailed M. Cruz-Collazo , Jean F. Ruiz-Calderón , Victor Mangas-Sanjuán , Suranganie Dharmawardhane , Jorge Duconge

MBQ-167 is a dual inhibitor of the Rho GTPases Rac and Cdc42 that has shown promising results as an anti-cancer therapeutic at the preclinical stage. This drug has been tested in vitro and in vivo in metastatic breast cancer mouse models. The aim of this study is to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK-PD) model of MBQ-167 to predict tumor growth inhibition following intraperitoneal (IP) administration in mice bearing Triple Negative and HER2+ mammary tumors. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the Simcyp V19 Animal Simulator. Our developed PBPK framework adequately describes the time course of MBQ-167 in each of the mouse tissues (e.g., lungs, heart, liver, kidneys, spleen, plasma) and tumor, since the predicted results were consistent with the experimental data. The developed PBPK-PD model successfully predicts tumor shrinkage in HER2+ and triple-negative breast tumors after the intraperitoneal administration of 1 and 10 mg/kg body weight (BW) dose level of MBQ-167 three times a week. The findings from this study suggest that MBQ-167 has a higher net effect and potency inhibiting Triple Negative mammary tumor growth compared to HER2+ and that liver metabolism is the major route of elimination of this drug.

中文翻译:

基于生理学的药代动力学/药代动力学模型MBQ-167预测小鼠的肿瘤生长抑制

MBQ-167是Rho GTPases Rac和Cdc42的双重抑制剂,在临床前阶段作为抗癌治疗剂已显示出令人鼓舞的结果。该药物已在转移性乳腺癌小鼠模型中进行了体外和体内测试。这项研究的目的是开发一种基于生理学的药代动力学/药效学(PBPK-PD)模型MBQ-167,以预测在腹膜内(IP)给予三阴性和HER2 +乳腺肿瘤小鼠的体内肿瘤生长抑制作用。使用Simcyp V19动物模拟器开发了PBPK和Simeoni肿瘤生长抑制(TGI)模型。我们的开发的PBPK框架充分描述了MBQ-167在每个小鼠组织(例如,肺,心脏,肝脏,肾脏,脾脏,血浆)和肿瘤中的时程,因为预测结果与实验数据一致。每周三次腹膜内施用1和10 mg / kg体重(BW)的MBQ-167剂量水平后,已开发的PBPK-PD模型成功预测了HER2 +和三阴性乳腺癌的肿瘤缩小。这项研究的发现表明,与HER2 +相比,MBQ-167具有更高的净效应和抑制三阴性乳腺肿瘤生长的功效,并且肝脏代谢是消除该药物的主要途径。
更新日期:2020-10-16
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