Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice Academic Article uri icon

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.

authors

  • Duconge-Soler, Jorge
  • Reig-López, Javier
  • Maldonado, María del Mar
  • Merino-Sanjuan, Matilde
  • Cruz-Collazo, Ailed M.
  • Ruiz-Calderón, Jean F.
  • Mangas-Sanjuán, Victor
  • Dharmawardhane, Suranganie
  • Duconge, Jorge

publication date

  • 2020

start page

  • 975

volume

  • 12

issue

  • 10