Multiscale Design of Cell‐Type–Specific Pharmacokinetic/Pharmacodynamic Models for Personalized Medicine: Application to Temozolomide in Brain Tumors

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.

Molecular mechanism matters: Benefits of mechanistic computational models for drug development

“…1) [13]. Detailed systems pharmacology models can be built and validated using in vitro data and pharmacokinetic studies in animals, and then converted into human- and disease-specific models [10, 24]. In order for these models to make clinically-relevant predictions, they must then be validated against human data to the maximum extent possible.…”

pH as a potential therapeutic target to improve temozolomide antitumor efficacy : A mechanistic modeling study

“…TMZ cellular PK‐PD was firstly represented by an Ordinary Differential Equations (ODE)‐based model . This model considers both an extra‐ and an intracellular compartment (Figure ).…”

“…TMZ is a prodrug that spontaneously converts into its metabolite 5‐(3‐methyltriazen‐1‐yl)imidazole‐ 4‐carboxamide (MTIC), which is subsequently degraded into 4‐amino‐5‐imidazole‐carboxamide (AIC)–an inactive metabolite and a methyldiazonium cation, the DNA‐methylating species. The methyldiazonium cation creates DNA adducts–a marker of TMZ pharmacodynamics (PD)–that trigger DNA damage responses and potentially induce cell death . Both TMZ and MTIC degradation rates are highly pH‐dependent as they exponentially increase and decrease with pH values, respectively …”

“…We here intend to investigate TMZ pH‐dependent pharmacokinetics (PK) and simplified pharamcodynamics (PD) in solid tumors through such hybrid mathematical modeling and validate the potential of pH as a therapeutic target to increase TMZ exposure benefit both in terms of efficacy and tolerability. We build on a previously published non‐spatial model of TMZ PK‐PD which has been incorporated into a spatial hybrid framework to analyze TMZ efficacy in a space‐ and pH‐dependent manner …”

Toward Personalized Medicine with Physiologically Based Pharmacokinetic Modeling

“…The new era of personalized medicine PBPK models have already helped in individualized treatment such as paracetamol overdose [13], individualization of medications in children [14], and application to temozolomide in brain tumors [15].…”