Limits...
Multiscale design of cell-type-specific pharmacokinetic/pharmacodynamic models for personalized medicine: application to temozolomide in brain tumors.

Ballesta A, Zhou Q, Zhang X, Lv H, Gallo JM - CPT Pharmacometrics Syst Pharmacol (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department 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.

No MeSH data available.


Related in: MedlinePlus

TMZ PK in U87 cell culture. (a–f) TMZ, MTIC, and AIC extra- and intracellular concentration–time profiles. Dots represent experimental data (mean ± SD); solid lines are the mathematical model best fit. (g) Medium pH time evolution during TMZ exposure. Experimental data points are the mean and SD of three independent experiments. (h) DNA adducts concentration simulated by the trained model. AIC, 4-amino-5-imidazole-carboxamide; MTIC, metabolite 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide; TMZ, temozolomide.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4017092&req=5

fig3: TMZ PK in U87 cell culture. (a–f) TMZ, MTIC, and AIC extra- and intracellular concentration–time profiles. Dots represent experimental data (mean ± SD); solid lines are the mathematical model best fit. (g) Medium pH time evolution during TMZ exposure. Experimental data points are the mean and SD of three independent experiments. (h) DNA adducts concentration simulated by the trained model. AIC, 4-amino-5-imidazole-carboxamide; MTIC, metabolite 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide; TMZ, temozolomide.

Mentions: Since TMZ metabolism is highly pH dependent, we monitored the medium pH () and found an initial increase followed by a return close to its initial value which was modeled as (Figure 3g):


Multiscale design of cell-type-specific pharmacokinetic/pharmacodynamic models for personalized medicine: application to temozolomide in brain tumors.

Ballesta A, Zhou Q, Zhang X, Lv H, Gallo JM - CPT Pharmacometrics Syst Pharmacol (2014)

TMZ PK in U87 cell culture. (a–f) TMZ, MTIC, and AIC extra- and intracellular concentration–time profiles. Dots represent experimental data (mean ± SD); solid lines are the mathematical model best fit. (g) Medium pH time evolution during TMZ exposure. Experimental data points are the mean and SD of three independent experiments. (h) DNA adducts concentration simulated by the trained model. AIC, 4-amino-5-imidazole-carboxamide; MTIC, metabolite 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide; TMZ, temozolomide.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4017092&req=5

fig3: TMZ PK in U87 cell culture. (a–f) TMZ, MTIC, and AIC extra- and intracellular concentration–time profiles. Dots represent experimental data (mean ± SD); solid lines are the mathematical model best fit. (g) Medium pH time evolution during TMZ exposure. Experimental data points are the mean and SD of three independent experiments. (h) DNA adducts concentration simulated by the trained model. AIC, 4-amino-5-imidazole-carboxamide; MTIC, metabolite 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide; TMZ, temozolomide.
Mentions: Since TMZ metabolism is highly pH dependent, we monitored the medium pH () and found an initial increase followed by a return close to its initial value which was modeled as (Figure 3g):

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department 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.

No MeSH data available.


Related in: MedlinePlus