Physiologically Based Pharmacokinetic Modeling
Physiologically Based Pharmacokinetic (PBPK) Modeling is a special type of
pharmacokinetics where physiology and anatomy of the animal or human body,
and the biochemistry of the chemical or chemicals of interest,
are incorporated into a conceptual model for computer simulation.
Unlike classical pharmacokinetics, PBPK modelling is a
powerful tool for many types of extrapolation, including species-to-species,
route-to-route, and dose-to-dose.
Our group has been involved in developing PBPK models and methodologies since 1991.
We have used PBPK modeling to predict ADME
(absorption, distribution, metabolism, and excretion)
and health risks for a diverse set of chemicals and
chemical mixtures.
A book on PBPK modelling has recently been published from our
laboratory in collaboration with others (Reddy et al., 2005).
Population Variability
We have recently been using Monte Carlo and Bayesian statistical methods (using Markov chain Monte Carlo)
with PBPK models to analyze the effects of population and dose variability and uncertainty on
the disposition of chemicals.
We have used these methods to perform forward dosimetry and
reverse dosimetry for risk assessment applications.
For these analyses we have been making use of
MCSim,
a software package written by
Frederic Bois, Don Maszle, Ken Revzan, Sophie Tillier, and Zeng Yuan.
Example
Below is a conceptual PBPK model for hexachlorobenzene (HCB) following iv (intravenous) or oral exposure.
The following figure illustrates results obtained from computer simulations embodying
the relevant equations associated with this model.
This plot shows model simulations (curves) and experimental data (symbols) of hexachlorobenzene
concentrations in the liver, muscle (slowly perfused compartment), and blood in the male
F344 rat in the time-course pharmacokinetics/liver foci bioassay with a dose of
0.03 mmol/kg/day. The arrow indicates when the partial hepatectomy (PH) was performed.
Representative Group Publications:
- Reisfeld, B., Mayeno, A., Lyons, M. Yang, R.S.H. Physiologically-Based Pharmacokinetic/Pharmacodynamic Modeling in _Computational Toxicology: Risk Assessment for Pharmaceutical and Environmental Chemicals_, S. Ekins, Editor. 2007, John Wiley & Sons: Hoboken, N.J.
- Yang, R.S.H., and Lu, Y. (2006). The application of PBPK modeling to risk assessment in _Environmental Health Risk Assessment_, M. G. Robson and W. A. Toscana, Editors. In press
- Lu, Y. and Yang, R.S.H. (2006). Introduction to physiologically based pharmacokinetic model construction: An example of 1,1,1-trichloroethane. Journal of Environmenal and Occupational Health. accepted
- Lu, Y., Lohitnavy, M., Reddy, M. B., Lohitnavy, O., Ashley, A., and Yang, R. S. (2006). An updated PBPK model for hexachlorobenzene: Incorporation of pathophysiological states following partial hepatectomy and hexachlorobenzene treatment. Toxicol Sci 91, 29-41.
- Reddy, M. B., Yang, R. S. H., Andersen, M. E., and Clewell, H., 3rd (2005). Physiologically Based Pharmacokinetic Modeling: Science and Applications. John Wiley & Sons, Hoboken, New Jersey.
- Dennison JE, Andersen ME, Yang RSH. (2005) Pitfalls and related improvements of in vivo gas uptake pharmacokinetic experimental systems. Inhal Toxicol. 17(11):539-48.
- Dennison JE, Bigelow PL, Mumtaz MM, Andersen ME, Dobrev ID, Yang RSH. (2005) Evaluation of potential toxicity from co-exposure to three CNS depressants (toluene, ethylbenzene, and xylene) under resting and working conditions using PBPK modeling. J Occup Environ Hyg. 2(3):127-35.
- Dennison JE, Bigelow PL, Andersen ME. (2004) Occupational exposure limits in the context of solvent mixtures, consumption of ethanol, and target tissue dose. Toxicol Ind Health. 20(6-10):165-75.
- Dennison JE, Andersen ME, Clewell HJ, Yang RSH. (2004) Development of a physiologically based pharmacokinetic model for volatile fractions of gasoline using chemical lumping analysis. Environ Sci Technol. 38(21):5674-81.
- Yang, R. S. H., Dennison, J. E., Andersen, M. E., Ou, Y. C., Liao, K. H., and Reisfeld, B. (2004). Physiologically based pharmacokinetic and pharmacodynamic modeling. In Mouse models of human cancer (E. C. Holland, ed.). John Wiley & Sons, Hoboken, New Jersey.
