The application of global sensitivity analysis in the development of a physiologically based pharmacokinetic model for m-xylene and ethanol co-exposure in humans

Abstract

Global sensitivity analysis (SA) was used during the development phase of a binary chemical physiologically based pharmacokinetic (PBPK) model used for the analysis of m-xylene and ethanol co-exposure in humans. SA was used to identify those parameters which had the most significant impact on variability of venous blood and exhaled m-xylene and urinary excretion of the major metabolite of m-xylene metabolism, 3-methyl hippuric acid. This analysis informed the selection of parameters for estimation/calibration by fitting to measured biological monitoring (BM) data in a Bayesian framework using Markov chain Monte Carlo (MCMC) simulation. Data generated in controlled human studies were shown to be useful for investigating the structure and quantitative outputs of PBPK models as well as the biological plausibility and variability of parameters for which measured values were not available. This approach ensured that a priori knowledge in the form of prior distributions was ascribed only to those parameters that were identified as having the greatest impact on variability. This is an efficient approach which helps reduce computational cost.

Keywords: PBPK modeling; global sensitivity analysis; human volunteer study; kinetics; xylene and ethanol coexposure.

FIGURE 1

Parameter main effects. Change in proportion of variance over time for venous blood concentration of m-xylene (CV_xyl): (A) without inhibition of m-xylene metabolism and (B) with inhibition of m-xylene metabolism. The broken lines represent the most dominant parameters over the entire simulation. Parameter abbreviations are listed in Table 4.

FIGURE 2

Lowry plot of the eFAST quantitative measure for variance in venous blood m-xylene concentration (CV_xyl). (A,C) Shows the total effects without inhibition of m-xylene metabolism and (B,D), with inhibition at 3 and 6 h after initiation of the simulation. Parameter abbreviations are listed in Table 4.

FIGURE 3

Parameter main effects. Change in proportion of variance over time for end-exhaled concentration of m-xylene (CX_ppm): (A) without inhibition of m-xylene metabolism and (B) with inhibition of m-xylene metabolism. The broken lines represent the most dominant parameters over the entire simulation. Parameter abbreviations are listed in Table 4.

FIGURE 4

Lowry plot of the eFAST quantitative measure for variance in venous blood m-xylene concentration (CX_ppm). (A,C) Shows the total effects without inhibition of m-xylene metabolism and (B,D), with inhibition at 3 and 6 h after initiation of the simulation. Parameter abbreviations are listed in Table 4.

FIGURE 5

Parameter main effects. Change in proportion of variance over time for urinary excretion of 3-methylhippuric acid (C_urine): (A) without inhibition of m-xylene metabolism and (B) with inhibition of m-xylene metabolism. The broken lines represent the most dominant parameters over the entire simulation. Parameter abbreviations are listed in Table 4.

FIGURE 6

Lowry plot of the eFAST quantitative measure for variance in venous blood m-xylene concentration (Curine). (A,C) Shows the total effects without inhibition of m-xylene metabolism and (B,D), with inhibition at 6 and 10 h after initiation of the simulation. Parameter abbreviations are listed in Table 4.

FIGURE 7

The full triangle symbols represent measured values for volunteer A without prior ethanol administration, and the solid line is the prediction. The full red circle symbols represent measured values with prior ethanol administration, and the red broken line is the prediction. (A) shows simulations without calibrated, and (B) with calibrated most sensitive parameters (MPY and PBAXYL). Parameter abbreviations are listed in Table 4.

FIGURE 8

The full triangle symbols represent measured values for volunteer E, without prior ethanol administration, and the solid line is the prediction. The full circle symbols represent measured values, with prior ethanol administration, and the broken line is the prediction. (A) Shows simulations without calibrated, and (B) with calibrated most sensitive parameters (MPY and PBAXYL). Parameter abbreviations are listed in Table 4.

FIGURE 9

The full triangle symbols represent measured values for volunteer H, without prior ethanol administration, and the solid line is the prediction. The full circle symbols represent measured values, with prior ethanol administration, and the broken line is the prediction. (A) Shows simulations without calibrated, and (B) with the calibrated most sensitive parameter (MPY). Parameter abbreviations are listed in Table 4.