Integrating “Omics” Data for Quantitative and Systems Pharmacology in Translational Oncology - Bioanalysis Advanced Materials Methods and Devices - page 191

Fig. 12.2 Schematic representation of a typical empiric PK-PD model. Drug concentrations are
frequently modeled by classical compartmental PK approaches. The plasma concentration-time
profile ( C A ) is then used in the biomarker response model and the tumor growth model to
determine the concentration-effect relationships

site of action and actual or simulated measures of concentration at the site of action
are rarely used. In some indications the plasma PK can be adequately related to
target effects [ 53 , 104 ]. However, in oncology, due to the heterogeneous nature of
tumors, this is likely to be an inaccurate assumption as we know that there are
several barriers to drug delivery in tumors and that these barriers can and will
change based on tumor type, location, stage of disease, or even from individual
lesion to lesion [ 51 , 84 ]. Tumor molecular, biochemical, and physiologic phenotype
can affect the distribution of drugs to tumor cells [ 51 , 56 , 84 ]. These differences in
disposition can lead to non-proportional relationships between plasma concentra-
tion and the concentration at the site of action leading to a poor understanding of the
concentration-effect relationships. Figure 12.2 is a schematic representation of a
PK-PD model structure commonly used in oncology to determine the nonclinical
PK-biomarker-tumor growth effect relationships [ 28 , 67 , 71 , 93 , 98 , 99 ]. Typically, a
compartmental model is used to describe the plasma distribution of a drug. It is
important to note, that in the classical compartmental pharmacokinetic model the
compartments do not carry any anatomic or physiologic meaning, making these
types of models data-based, primarily confined to describing plasma concentration
and highly limited in the ability to scale between species or extrapolate doses.
To improve the scaling and extrapolation of pharmacokinetics, more complex,
mechanistically grounded models can be employed, such as p hysiologically b ased
p harmaco k inetic (PBPK) models. In contrast

to compartmental models, the