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

Javier Reig-López1, María Del Mar Maldonado2, Matilde Merino-Sanjuan1,3

  • 1Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, 46100 Burjassot, Valencia, Spain.

Pharmaceutics
|October 20, 2020
PubMed

Insights

MBQ-167, a dual Rho GTPase inhibitor, effectively reduced triple-negative breast tumors more than HER2+ tumors in mice. A PBPK-PD model accurately predicted this tumor growth inhibition, with liver metabolism as the primary elimination route.

Area of Science:

  • Pharmacology and Toxicology
  • Cancer Therapeutics
  • Computational Biology

Background:

  • MBQ-167 is a dual inhibitor of Rho GTPases Rac and Cdc42, showing preclinical anti-cancer potential.
  • Metastatic breast cancer models in mice have demonstrated promising results for MBQ-167.

Purpose of the Study:

  • To develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK-PD) model for MBQ-167.
  • To predict tumor growth inhibition (TGI) in triple-negative and HER2+ mammary tumors after intraperitoneal (IP) administration in mice.

Main Methods:

  • Utilized Simcyp V19 Animal Simulator to develop PBPK and Simeoni TGI models.
  • Validated the PBPK model by comparing predicted MBQ-167 concentrations with experimental data in various mouse tissues and tumors.
  • Employed the PBPK-PD model to simulate tumor response to IP administration of MBQ-167.

Main Results:

  • The PBPK framework accurately described MBQ-167's time course in mouse tissues and tumors.
  • The PBPK-PD model successfully predicted tumor shrinkage in both HER2+ and triple-negative breast tumors.
  • MBQ-167 demonstrated greater potency and net effect in inhibiting triple-negative mammary tumors compared to HER2+ tumors.

Conclusions:

  • MBQ-167 exhibits differential efficacy against distinct breast cancer subtypes.
  • Liver metabolism is identified as the principal pathway for MBQ-167 elimination.
  • The developed PBPK-PD model serves as a valuable tool for predicting MBQ-167's anti-cancer effects.
Keywords:
MBQ-167Rac inhibitorbreast cancerphysiologically based pharmacokinetic modeling

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