Physiologically based pharmacokinetic evaluation

Levitt, D.G., The use of a physiologically based pharmacokinetic model to evaluate deconvolution measurements of systemic absorption, BMC Clin. Pharmacol, 3,1, 2003. 

Peters, S.A. (2008) Evaluation of a generic physiologically based pharmacokinetic model for lineshape analysis. Clinical... 

In attempting to correlate the human and animal data, Nolan et al. (1984) validated a physiologically based pharmacokinetic model for 1,1,1-trichloroethane. The model predicted greater absorption, blood levels and metabolism of 1,1,1-trichloroethane in rodents than in humans. On the basis of toxicokinetic data, rats were suggested to be a better model than mice to evaluate potential health effects in humans. 

The UEL for reproductive and developmental toxicity is derived by applying uncertainty factors to the NOAEL, LOAEL, or BMDL. To calculate the UEL, the selected UF is divided into the NOAEL, LOAEL, or BMDL for the critical effect in the most appropriate or sensitive mammalian species. This approach is similar to the one used to derive the acute and chronic reference doses (RfD) or Acceptable Daily Intake (ADI) except that it is specific for reproductive and developmental effects and is derived specifically for the exposure duration of concern in the human. The evaluative process uses the UEL both to avoid the connotation that it is the RfD or reference concentration (RfC) value derived by EPA or the ADI derived for food additives by the Food and Drug Administration, both of which consider all types of noncancer toxicity data. Other approaches for more quantitative dose-response evaluations can be used when sufficient data are available. When more extensive data are available (for example, on pharmacokinetics, mechanisms, or biological markers of exposure and effect), one might use more sophisticated quantitative modeling approaches (e.g., a physiologically based pharmacokinetic or pharmacodynamic model) to estimate low levels of risk. Unfortunately, the data sets required for such modeling are rare. 

Hazard identification is the step in the risk assessment that qualitatively characterizes the inherent toxicity of a chemical. Scientific data are evaluated to establish a possible causal relationship between the occurrence of adverse health effects and chemical exposure. This step includes characterization of acute, subchronic, and chronic effects the potential for local versus systemic effects the influence of the route of exposure the relevance, to humans, of effects seen in animals an evaluation of the biological importance of the observed effects the likelihood of the effects occurring under certain conditions and the potential implications for public health. This step should be based on a thorough review of all the data that may provide information that is relevant to evaluating the potential chemical hazard. This may include data describing the effects on a variety of test animals, in vitro studies that characterize mechanisms of toxicity, metabolism, physiologically based pharmacokinetic studies, structure-activity relationships, short-term human studies, and epidemiological studies. Animal studies may focus on particular types of effects and may include reproductive toxicity studies,... 

Germani, M., Crivori, P., Rocchetti, M., Burton, P.S., Wilson, A.G.E., Smith, M.E. and Poggesi, I. (2007) Evaluation of a basic physiologically-based pharmacokinetic model for simulating... 

Cai, H., Stoner, C., Reddy, A., Freiwald, S., Smith, D., Winters, R., Stankovic, C. and Surendran, N. (2006) Evaluation of an integrated in vitro - in silico PBPK (physiologically-based pharmacokinetic) model to provide estimates of human bioavailability. International Journal of Pharmaceutics, 308, 133-139. 

Clark, L. H., Woodrow Setzer, R., and Barton, H. A. (2004). Framework for evaluation of physiologically-based pharmacokinetic models for use in safety or risk assessment. Risk Anal 24, 1697-1717. 

Thrall, K.D. and Woodstock, A.D., 2002, Evaluation of the dermal absorption of aqueous toluene in F344 rats using real-time breath analysis and physiologically based pharmacokinetic modeling, J. Toxicol. Environ. Health A, 65, 2087-2100. 

Thiel C, Schneckener S, Krauss M, Ghallab A, Hofmann U, Kanacher T, Zellmer S, Gebhardt R, Hengstler JG, Kuepfer L. 2014. A systematic evaluation of the use of physiologically based pharmacokinetic modeling for cross-species extrapolation. J Pham Sci 104 191-206. 

Parrott, N Paquereau, N Coassolo, P Lave, Th. An evaluation of the utility of physiologically based models of pharmacokinetics in early drug discovery. f Pharm. Sci. 2005, 94, 2327-2343. 

Parrott N, Paquereau N, Coassolo P, and Lave T. An Evaluation of the Utility of Physiologically Based Models of Pharmacokinetics in Early Discovery. JPharm... 

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