Reducing whole body physiologically based pharmacokinetic models using global sensitivity analysis: diazepam case study.

There are situations in drug development where one may wish to reduce the dimensionality and complexity of whole body physiologically based pharmacokinetic models. A technique for formal reduction of such models, based on global sensitivity analysis, is suggested. Using this approach mean and variance of tissue(s) and/or blood concentrations are preserved in the reduced models. Extended Fourier amplitude sensitivity test (FAST), a global sensitivity technique, takes a sampling approach, acknowledging parameter variability and uncertainty, to calculate the impact of parameters on concentration variance. We used existing literature rules for formal model reduction to identify all possible smaller dimensionally models. To discriminate among those competing mechanistic models extended FAST was used, whereby we treated model structural uncertainty as another factor contributing to the overall uncertainty. A previously developed 14 compartment whole body physiologically based model for diazepam disposition in rat was reduced to three alternative reduced models, with preserved arterial mean and variance concentration profiles.