PD relationship and thus make a better prediction of the time course of drug effects resulting from a certain dose regimen for the compound of interests. Furthermore, PBPK models in combination with absorption simulation and quantitative structure-activity relationship (QSAR) approaches will bring us closer to a full prediction of drug disposition for pharmaceutical new entities, and help streamline the selection of lead drug candidate in the drug discovery process (van de Waterbeemd and Gifford 2003). Lastly, unlike empirical noncompartmental and compartmental pharmacokinetics, PBPK modeling is a powerful tool for extrapolation, be it for inter-species, inter-routes, inter-doses, inter-life stages, etc.
The concepts of PBPK had its embryonic development in the 1920s and 1940s; for a more detailed early history, the readers are referred to a review (Yang et al. 2004) and a recently published book (Reddy et al. 2005). PBPK modeling blossomed and flourished in the late 1960s and early 1970s in the chemotherapeutic area mainly due to the efforts of investigators with expertise in chemical engineering process design and control. Two notable pioneers in this development are Dr. Kenneth B. Bischoff, then at University of Texas, Austin, TX, and Dr. Robert Dedrick of Biomedical Engineering and Instrumentation Branch, Division of Research Services, National Institute of Health, Bethesda, MD. Two timeless publications by these investigators are, respectively, “Drug Distribution in Mammals” (Bischoff and Brown, 1966) and “Animal Scale-Up” (Dedrick, 1973); these papers are highly recommended to those who are interested in PBPK modeling. In the mid 1980s, two papers on PBPK modeling of styrene and methylene chloride (Ramsey and Andersen 1984; Andersen et al. 1987) started yet another “revolution” in the toxicology and risk assessment arena. Today, there are more than 700 publications directly related to PBPK modeling on industrial chemicals, drugs, environmental pollutants, and simple and complex chemical mixtures (Reddy et al. 2005).
A PBPK model, graphically illustrated in Figure C-1, reflects the incorporation of basic physiology and anatomy. The compartments actually correspond to anatomic entities such as liver, lung, …etc., and the blood circulation conforms to the basic mammalian physiology. In this specific model, an actual published example on methylene chloride, it is quite obvious that the exposure route of interest is inhalation because the lung and gas exchange compartments are prominently displayed with intake (CI) and exhalation (CX) vapor concentrations indicated. Oral and/or dermal exposures may be added easily to the GI tract compartment or general venous circulation, respectively. Some tissues (e.g., richly (poorly) or slowly (rapidly) perfused tissues in Figure C-1) are “lumped” together because there is insufficient evidence to conclude that the component tissues in each of these compartment are kinetically distinct enough, for the specific chemical, to warrant individual separate compartments.