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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 brain tumor patients. (a) TMZ blood concentration–time profile. Solid line is the forcing function best fit. Open circles are TMZ plasma concentration measurements in patients.31 (b–e) TMZ interstitial (b) and intracellular (c) concentration–time profiles in the normal brain (solid lines) and brain tumor (dashed lines). Blue color corresponds to the model calibrated with naive parameters, whereas black color represents the best-fit model with estimated parameters. In (b), open diamonds are TMZ normal brain concentrations from microdialysis measurements in patients,31 which are shown in greater details in the inset, together with TMZ normal brain interstitial concentration best-fit profile. (f) Global analysis of parameter sensitivity on drug efficacy in brain tumor (see Results and Methods). PK, pharmacokinetics; TMZ, temozolomide.
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fig5: TMZ PK in brain tumor patients. (a) TMZ blood concentration–time profile. Solid line is the forcing function best fit. Open circles are TMZ plasma concentration measurements in patients.31 (b–e) TMZ interstitial (b) and intracellular (c) concentration–time profiles in the normal brain (solid lines) and brain tumor (dashed lines). Blue color corresponds to the model calibrated with naive parameters, whereas black color represents the best-fit model with estimated parameters. In (b), open diamonds are TMZ normal brain concentrations from microdialysis measurements in patients,31 which are shown in greater details in the inset, together with TMZ normal brain interstitial concentration best-fit profile. (f) Global analysis of parameter sensitivity on drug efficacy in brain tumor (see Results and Methods). PK, pharmacokinetics; TMZ, temozolomide.

Mentions: Naive scale-up overestimated TMZ concentrations in the normal brain and tumor as AUC values of best-fit TMZ interstitial and intracellular concentrations were on average 5.1-fold greater than the ones of the human data-fitted model (Figure 5a–e). Concerning the human data-fitted model, the ratio was 2.8-fold lower than which suggested a disruption of the BBB in the tumor region as in the mouse study. Interestingly, the ratios between TMZ interstitial and intracellular AUC were the same in the preclinical and human data-fitted simulations. As a consequence of having inferred from the mouse study the ratios between brain and tumor transport parameters, TMZ intracellular AUC ratio between brain and tumor was close to the preclinical one as it was equal to 1.7, leading to a 1.7-fold higher final DNA adduct concentration in the tumor compared to the normal brain (Figure 5). The %CV of parameters were relatively high due to the inherent variability of the clinical data that was utilized for parameter estimation (Figure 5a,b; Table 1). Next, we performed a global sensitivity analysis to determine the important parameter regarding the efficacy of TMZ computed as the AUC of DNA adduct concentration in the tumor. The parameter which corresponds to the BBB had the highest influence followed by kclear, TMZ clearance rate in the plasma (Figure 5f).


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 brain tumor patients. (a) TMZ blood concentration–time profile. Solid line is the forcing function best fit. Open circles are TMZ plasma concentration measurements in patients.31 (b–e) TMZ interstitial (b) and intracellular (c) concentration–time profiles in the normal brain (solid lines) and brain tumor (dashed lines). Blue color corresponds to the model calibrated with naive parameters, whereas black color represents the best-fit model with estimated parameters. In (b), open diamonds are TMZ normal brain concentrations from microdialysis measurements in patients,31 which are shown in greater details in the inset, together with TMZ normal brain interstitial concentration best-fit profile. (f) Global analysis of parameter sensitivity on drug efficacy in brain tumor (see Results and Methods). PK, pharmacokinetics; TMZ, temozolomide.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: TMZ PK in brain tumor patients. (a) TMZ blood concentration–time profile. Solid line is the forcing function best fit. Open circles are TMZ plasma concentration measurements in patients.31 (b–e) TMZ interstitial (b) and intracellular (c) concentration–time profiles in the normal brain (solid lines) and brain tumor (dashed lines). Blue color corresponds to the model calibrated with naive parameters, whereas black color represents the best-fit model with estimated parameters. In (b), open diamonds are TMZ normal brain concentrations from microdialysis measurements in patients,31 which are shown in greater details in the inset, together with TMZ normal brain interstitial concentration best-fit profile. (f) Global analysis of parameter sensitivity on drug efficacy in brain tumor (see Results and Methods). PK, pharmacokinetics; TMZ, temozolomide.
Mentions: Naive scale-up overestimated TMZ concentrations in the normal brain and tumor as AUC values of best-fit TMZ interstitial and intracellular concentrations were on average 5.1-fold greater than the ones of the human data-fitted model (Figure 5a–e). Concerning the human data-fitted model, the ratio was 2.8-fold lower than which suggested a disruption of the BBB in the tumor region as in the mouse study. Interestingly, the ratios between TMZ interstitial and intracellular AUC were the same in the preclinical and human data-fitted simulations. As a consequence of having inferred from the mouse study the ratios between brain and tumor transport parameters, TMZ intracellular AUC ratio between brain and tumor was close to the preclinical one as it was equal to 1.7, leading to a 1.7-fold higher final DNA adduct concentration in the tumor compared to the normal brain (Figure 5). The %CV of parameters were relatively high due to the inherent variability of the clinical data that was utilized for parameter estimation (Figure 5a,b; Table 1). Next, we performed a global sensitivity analysis to determine the important parameter regarding the efficacy of TMZ computed as the AUC of DNA adduct concentration in the tumor. The parameter which corresponds to the BBB had the highest influence followed by kclear, TMZ clearance rate in the plasma (Figure 5f).

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