Multiscale design of cell-type-specific pharmacokinetic/pharmacodynamic models for personalized medicine: application
A Ballesta1, Q Zhou2, X Zhang1
1Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, USA.
Abstract:
Optimizing anticancer therapeutics needs to account for variable drug responses in heterogeneous cell populations within the tumor as well as in organs of toxicity. To address cell heterogeneity, we propose a multiscale modeling approach-from in vitro to preclinical and clinical studies-to develop cell-type-specific pharmacokinetic-pharmacodynamic (PK-PD) models. A physiologically based mechanistic modeling approach integrating data from aqueous solutions, U87 glioma cells, mice, and cancer patients was utilized to characterize the brain disposition of temozolomide (TMZ), the cornerstone of chemotherapy against glioblastoma multiforme. The final model represented intracellular normal brain and brain tumor compartments in which TMZ pH-dependent conversion to the DNA-alkylating species leads to the formation of DNA adducts that serve as an entry point for a PD model. This multiscale protocol can be extended to account for TMZ PK-PD in different cell populations, thus providing a critical tool to personalize TMZ-based chemotherapy on a cell-type-specific basis.
Insights
This study introduces a multiscale modeling approach to personalize anticancer drug treatment by accounting for cell type differences. This pharmacokinetic-pharmacodynamic (PK-PD) model optimizes temozolomide (TMZ) chemotherapy for glioblastoma.
Area of Science:
- Pharmacology
- Oncology
- Biomedical Engineering
Background:
- Anticancer drug efficacy varies due to cell heterogeneity within tumors and toxicity in organs.
- Personalized chemotherapy requires understanding drug disposition and effects at a cellular level.
Purpose of the Study:
- To develop cell-type-specific pharmacokinetic-pharmacodynamic (PK-PD) models for optimizing anticancer therapeutics.
- To characterize the brain disposition and PK-PD of temozolomide (TMZ) in glioblastoma using a multiscale approach.
Main Methods:
- A physiologically based mechanistic modeling approach was employed, integrating data from in vitro studies, U87 glioma cells, preclinical animal models, and human clinical trials.
- The model characterized temozolomide (TMZ) disposition in normal brain and brain tumor compartments.
- A pH-dependent conversion of TMZ to DNA-alkylating species and subsequent DNA adduct formation were modeled as the pharmacodynamic (PD) entry point.
Main Results:
- The developed multiscale model successfully characterized the brain disposition of temozolomide (TMZ).
- The model elucidated the intracellular conversion of TMZ and its DNA-alkylating effects within different brain compartments.
- The PK-PD modeling approach demonstrated the potential for cell-type-specific analysis.
Conclusions:
- The multiscale modeling protocol provides a framework for understanding and predicting temozolomide (TMZ) PK-PD in heterogeneous cell populations.
- This approach serves as a critical tool for personalizing temozolomide-based chemotherapy for glioblastoma on a cell-type-specific basis.
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