Dispositional studies, experimental models

Preliminary studies using the IPPSF have shown that compounds such as the cancer chemotherapeutic agents cisplatin and carboplatin and the antibiotics tetracycline and doxycycline readily distribute into the skin following intravascular administration. Also, compounds such as parathion, 1-aminobenzo-triazole (ABT), and 25-hydroxyvitamin D are bioactivated in the skin following intravascular administration in the IPPSF. This demonstrates a role for the IPPSF as an ideal experimental model for studying the disposition of xenobiotics that are... 

Model systems needed for particular studies are listed in Figure 5.2. In addition, in silico models are developed to predict drug behaviors based on physicochemical properties of drugs or drug candidates, crystal structures of a protein (an enzyme or a transporter), and database of ADME properties generated in laboratories. Therefore, experimental models are important for ADME studies. The objective of this chapter is to discuss strategy and applications of experimental models in drug metabolism and disposition. 

This example shows that (1) the mechanistic PK/PD model developed based on literature data of rHu-EPO and predinical information of a new ERA is suitable to provide a better quantification and prediction of the drug disposition and the time course of hemoglobin in adult healthy subjects, and (2) this model can be used to optimize the design of the Phase I studies of new ERAs, with respect to key design features (number of dose levels, selection of dose levels, number of subjects per dose level, PK/PD sampling times). In this way, a quantitative risk-benefit assessment can be obtained by determining the probability of success of a Phase I study with new ERA, conditional on a certain experimental design. 

Drug discovery and development remain as complicated models-based experimental scientific exploration. These models provide a variety of data that range from in vitro systems to in vivo animal species and healthy human subjeets that should predict the behavior of a drug in patients. These data either deal with a particular aspect of drug metabolism such as permeability and transporter properties as derived from Caco-2 models or provide the entire distributional and dispositional properties of a drug as obtained from a radioearbon human ADME study. Figure 5.6 is a summary of the meehanistie input and... 

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