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Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice.


ABSTRACT: 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.

SUBMITTER: Reig-Lopez J 

PROVIDER: S-EPMC7602742 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice.

Reig-López Javier J   Maldonado María Del Mar MDM   Merino-Sanjuan Matilde M   Cruz-Collazo Ailed M AM   Ruiz-Calderón Jean F JF   Mangas-Sanjuán Victor V   Dharmawardhane Suranganie S   Duconge Jorge J  

Pharmaceutics 20201015 10


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. PBP  ...[more]

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