Physiologically-based pharmacokinetic validation

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... 

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. 

Much of the research efforts in risk assessment are therefore aimed at reducing the need to use these default uncertainty factors, although the risk assessor is limited by data quality of the chemical of interest. With sufficient data and the advent of sophisticated and validated physiologically based pharmacokinetic models and biologically based dose-response models (Conolly and Butterworth, 1995), these default values can be replaced with science-based factors. In some instances there may be sufficient data to be able to obtain distributions rather than point estimates. 

Liao KH. 2004. Development and validation of a hybrid reaction network/physiologically based pharmacokinetic model of benzo[a]pyrene and its metabolites. PhD dissertation, Department of Chemical and Biological Engineering, Colorado State University, Fort Collins (CO). 

Keys DA, Bruckner JV, Muralidhara S, Fisher JW. Tissue dosimetry expansion and cross-validation of rat and mouse physiologically based pharmacokinetic models for trichloroethylene. Toxicol Sci 2003 76 35-50. 

Physiologic model-physiologically based pharmacokinetic model (PB/PK) A physiologically based model for Gl transit and absorption in humans is presented. The model can be used to study the dependency of the fraction dose absorbed (Fabs) of both neutral and ionizable compounds on the two main physico-chemical input parameters [the intestinal permeability coefficient (Pint) and the solubility in the intestinal fluids (Sint)] as well as the physiological parameters, such as the gastric emptying time and the intestinal transit time. For permeability-limited compounds, the model produces the established sigmoidal dependence between Fabs and Pnt. In case of solubility-limited absorption, the model enables calculation of the critical mass-solubility ratio, which defines the onset of nonlinearity in the response of fraction absorbed to dose. In addition, an analytical equation to calculate the intestinal permeability coefficient based on the compound s membrane affinity and MW was used successfully in combination with the PB-PK model to predict the human fraction dose absorbed of compounds with permeability-limited absorption. Cross-validation demonstrated a root-mean-square prediction error of 7% for passively absorbed compounds. 

Eventually, the toxicokinetic data, together with the distribution data, are very useful for the validation of physiologically based pharmacokinetic modeling (PBPK). " These models are needed because the experiments that were discussed in this chapter can never be performed in humans, whereas extrapolation of the results obtained in these animal experiments to man is stiU the ultimate goal of these investigations. 

Physiologically based pharmacokinetic (PB-PK) models for some JP-8 components have been developed to understand the relationship between vapor concentrations and accumulation in tissue and blood compartments. When appropriately developed and validated, PB-PK models can provide a time course of distribution of a chemical or its metabolites in tissues and show the effect of changingphysiologic characteristics on plasma and tissue concentrations. PB-PK models have been applied to predict toxicokinetic parameters and to scale dose in different species. 

Poulin P. 2015b. Albumin and uptake of drugs in cells additional validation exercises of a recently published equation that quantifies the albumin-facUitated uptake mechanism(s) in physiologically based pharmacokinetic and pharmacodynamic modeling research. J Pharm Sci 104. doi 10.1002/jps.24676. 

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