Addressing Uncertainty and Variability in Physiologically Based Pharmacokinetic Models. A. Roy and P. G. Georgopoulos, Environmental and Occupational Health Sciences Institute, Rutgers University, New Brunswick, NJ
Pharmacokinetic variability can influence the toxic effect of a chemical by affecting the extent to which the chemical is absorbed, distributed, bioactivated (or deactivated), and excreted. One of the main advantages of using physiologically based pharmacokinetic (PBPK) models to describe pharmacokinetic variability is that parameters in these models are physiologically meaningful, and can in principle be estimated by independent methods. Generally, more information is available on chemical independent PBPK model parameters (such as blood flows and tissue volume) than on chemical specific parameters (such as partition coefficients and metabolic constants. However, there will always be some uncertainty associated with the values of model parameters for an individual due to random error in the data used to estimate the parameter, intra-individual variability, and assumptions that are inherent in any model of physical processes. Furthermore, inter-individual variability among individuals in a population will lead to a distribution of values for a given PBPK model parameter. Intra- and inter-individual pharmacokinetic variability have been described by population pharmacokinetic models that incorporate a hierarchy of probability distribution functions. This paper addresses the effect of uncertainty and variability in PBPK model parameters on the prediction of dose and dose surrogates for individuals and populations. Uncertainty analysis of a PBPK model is generally performed using Monte Carlo simulation with model parameters specified by idealized distributions. The assumptions underlying commonly used distributions are discussed, and the consequences of the commonly applied assumption of independence assumption are demonstrated. Finally, the application of numerical Bayesian methods for reducing uncertainty is presented.
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