Separating uncertainty and physiological variability in human PBPK modelling: The example of 2-propanol and its metabolite acetone

Abstract

Parameter uncertainty and interindividual variability in the predictions of a generic human physiologically based pharmacokinetic (PBPK) model were separated by means of nested Monte Carlo simulations. Separate information on uncertainty and variability can help decision makers to identify whether they should focus on identification of sensitive individuals rather than on additional research to obtain more accurate estimates for particular parameters. In this study, the concentration of acetone in human blood was simulated during and after 4h of exposure to 2-propanol via air. It was shown that the influence of interindividual variability and uncertainty varies over time, from the uptake phase, via a steady-state phase, into the elimination phase. During the uptake phase, interindividual variability played a significant role in the predicted variation of acetone concentrations in blood, with variability up to a factor of 2-3 (90th/10th percentile ratio). After exposure ceased, the parameter uncertainty increased up to a factor of 100 after 16h, whereas variability remained unchanged. Parameter importance analysis indicated that variability in human physiology had the largest influence on predicted acetone concentrations in blood during exposure. Uncertainty in the metabolic rate of acetone was most important after the exposure had ceased and overruled variability.