Physiologically-based pharmacokinetic development

Simulation methods have also been developed that include physiologically based pharmacokinetic modeling (PBPK) and methods such as Cloe PK, OMPPPlus, GastroPlus , SimCYP , and others [122] that are described elsewhere in this book. It is likely that the computational metabolism predictions could be integrated with these to assist in deriving more accurate predictions of human pharmacokinetic parameters. 

Rowland M, Balant L, Peck C. Physiologically based pharmacokinetics in drug development and regulatory science a workshop report (Georgetown University, Washington, DC, May 29-30, 2002). AAPS PharmSci 2004 6 E6. 

Clewell HJ 3rd, Gentry PR, Covington TR, Gearhart JM. Development of a physiologically based pharmacokinetic model of trichloroethylene and its metabolites for use in risk assessment. Environ Health Perspect 2000 May 108 Suppl 2 283-305. 

Charnick SB, Kawai R, Nedelman JR, Lemaire M, Niederberger W, Sato H. Perspectives in pharmacokinetics. Physiologically based pharmacokinetic modeling as atoolfor drug development./P/jarmacokmefTEop/jarm 1995 Apr 23(2) 217-29. Review. 

Theil FP, Guentert TW, Haddad S, Poulin P. Utility of physiologically based pharmacokinetic models to drug development and rational drug discovery candidate selection. Toxicol Lett 2003 Feb 18 138(l-2) 29-49. Review. 

The Chemical Manager and Authors acknowledge the contribution of Dr. Ted W. Simon, U.S. EPA, in applying physiologically-based pharmacokinetic modeling to the development of minimal risk levels for trichloroethylene. 

Physiologically based pharmacokinetic models provide a format to analyze relationships between model parameters and physicochemical properties for a series of drug analogues. Quantitative structure-pharmacokinetic relationships based on PB-PK model parameters have been pursued [12,13] and may ultimately prove useful in the drug development process. In this venue, such relationships, through predictions of tissue distribution, could expedite drug design and discovery. 

Absorbed lead is distributed in various tissue compartments. Several models of lead pharmacokinetics have been proposed to characterize such parameters as intercompartmental lead exchange rates, retention of lead in various pools, and relative rates of distribution among the tissue groups. See Section 2.3.5 for a discussion of the classical compartmental models and physiologically based pharmacokinetic models (PBPK) developed for lead risk assessments. 

FUN tool is a new integrated software based on a multimedia model, physiologically based pharmacokinetic (PBPK) models and associated databases. The tool is a dynamic integrated model and is capable of assessing the human exposure to chemical substances via multiple exposure pathways and the potential health risks (Fig. 9) [70]. 2-FUN tool has been developed in the framework of the European project called 2-FUN (Full-chain and UNcertainty Approaches for Assessing Health Risks in FUture ENvironmental Scenarios www.2-fun.org). 

Other major early contributions of biochemical engineering have been in the development of the artificial kidney and physiologically based pharmacokinetic models. The artificial kidney has been literally a lifesaver. Pharmacokinetic models divide the body of an animal or human into various compartments that act as bioreactors. These mathematical models have been used very successfully in developing therapeutic strategies for the optimal delivery of chemotherapeutic drugs and in assessing risk from exposure to toxins. 

Andersen ME (1995) Development of physiologically based pharmacokinetic and physiologically based pharmacodynamic models for applications in toxicology and risk assessment. Toxicol Lett 79 35-44... 

Mirfazaelian A, Kim K, Anand SS, Kim HJ, Tomero-Velez R, Bruckner JV, Fisher JW (2006) Development of a physiologically based pharmacokinetic model for deltamethrin in the adult male Sprague-Dawley rat. Toxicol Sci 93(2) 432-442... 

Physiologically based pharmacokinetic models regarding phenol have typically been developed as part of the attempt to understand the toxicity of benzene, of which phenol is the primary metabolite. Human exposure to... 

Physiologically Based Toxicokinetic (PBTK) models are derived similarly to Physiologically Based Pharmacokinetic (PBPK) models, which have been used for a number of years in the development of medicinal drugs. They describe the rat or man as a set of tissue compartments, i.e., liver, adipose tissues, poorly perfused tissues, and richly perfused tissues along with a description of metabolism in the liver. In case of volatile organic compounds a description of gas exchange at the level of the lung is included, see also Section 4.3.6. 

Clewell, H.f, Reddy, M.B., Lave, T. and Andersen, M.E. (2008) Physiologically based pharmacokinetic modeling, in Preclinical Development Handbook ... 

Physiologically-based pharmacokinetic (PBPK) models have been developed for a number of drugs and chemicals, in order to better understand and simulate the dynamics of those compounds in the body. Advances made to date indicate that valid PBPK models can accurately predict the... 

Leung HW. 1991. Development and utilization of physiologically based pharmacokinetic models for toxicological applications. J Toxicol Environ Health 32 247-267. 

Tardif et al. (1992, 1993 a, 1997) have developed a physiologically based toxicokinetic model for toluene in rats (and humans—see Section 4.1.1). They determined the conditions under which interaction between toluene and xylene(s) occurred during inhalation exposure, leading to increased blood concentrations of these solvents, and decreased levels of the hippurates in urine. Similar metabolic interactions have been observed for toluene and benzene in rats (Purcell et al., 1990) toluene inhibited benzene metabolism more effectively than the reverse. Tardif et al. (1997) also studied the exposure of rats (and humans) to mixtures of toluene, we/a-xylene and ethylbenzene, using their physiologically based pharmacokinetic model the mutual inhibition constants for their metabolism were used for simulation of the human situation. 

Tardif et al. (1997) developed a physiologically based pharmacokinetic model for zneio-xylene in rats and humans. They also simulated interactions between weto-xylene, toluene and ethylbenzene, and showed that for exposures at air concentrations remaining within the permissible range for a mixture, biologically significant interactions at the pharmacokinetic level would not occur. 

Peng, B., Andrews, J., Nestorov, I., Brennan, B., Nicklin, P. and Rowland, M. (2001) Tissue distribution and physiologically based pharmacokinetics of antisense phosphorothioate oligonucleotide ISIS 1082 in rat. Antisense Nucleic Acid Drug Develop., 11, 15-27. 

In fact, physiologically based pharmacokinetic models are similar to environmental fate models. In both cases we divide a complicated system into simpler compartments, estimate the rate of transfer between the compartments, and estimate the rate of transformation within each compartment. The obvious difference is that environmental systems are inherently much more complex because they have more routes of entry, more compartments, more variables (each with a greater range of values), and a lack of control over these variables for systematic study. The discussion that follows is a general overview of the transport and transformation of toxicants in the environment in the context of developing qualitative and quantitative models of these processes. 

PFOA Serum PFOA Use of animal toxicology and physiologically based pharmacokinetic modeling to develop biomarker-response relationship in animals Chapter 5... 

Poulin and Krishnan (1995) developed a method to predict tissue blood PCs for incorporation into physiologically based pharmacokinetic (PBPK) models. Tissue blood partitioning was calculated as an additive function of partitioning into the water, neutral lipids and phospholipids constituent of individual tissues. These were calculated using published values for lipid and water content of tissues and the octanol-water PC of the compounds. Poulin and Krishnan (1998 1999) used this method to predict tissue blood PCs that were subsequently incorporated into a quantitative structure-toxicokinetic model. The prediction of tissue plasma PCs to describe distribution processes and as input parameters for PBPK models has been extensively researched by Poulin and coworkers a great deal of further information can be obtained from their references (Poulin and Theil, 2000 Poulin et al., 2001 Poulin and Theil, 2002a Poulin and Theil, 2002b). 

Blesch, K.S. et al. Clinical pharmacoki-netic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development the capedtabine experience. Invest New Drugs 2003, 21 195-223. 

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