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Reducing PBPK Models Using Global Sensitivity Analysis and Benefit/Cost Criterion

I. Gueorguieva, I. Nestorov, M. Rowland

Currently, PBPK models are used mainly in preclinical drug development to predict human PK extrapolated from animal studies. Due to their complexity these models are not used in later development phases. However, if a PBPK model can be formally reduced but still preserve its physiological meaning and the price, i.e. information loss is explicitly stated, this reduced yet still physiological model can be taken further to Phase I and even Phase II and III. Such a continuous flow of information will improve our knowledge and understanding throughout drug development, which will inevitably better our decision making process. A successful and complete PBPK model should account for the parametric variability and uncertainty as well as recognize structural model uncertainty. Although a number of studies address the issue of propagating parametric variability (mainly by Monte Carlo simulations), structural uncertainty has not been extensively investigated. Sensitivity analysis (SA) studies how the variance of the plasma concentration or pharmacological effect can be apportioned qualitatively or quantitatively to different sources of variation. SA is used to increase the confidence in the model and its predictions by providing an understanding how the model responds to any changes, be they parameters or structure. Carrying out SA is a prerequisite to any model building. Global sensitivity analysis (GLS) is a variance-based method, which takes a sampling approach and the variability and uncertainty range assigned to PK parameters reflects our knowledge of them. All the parameters are varied simultaneously and the sensitivity is measured over the entire range of each input parameter. The aim of this study was to find an optimal (smaller dimensionally) physiologically based pharmacokinetic (PBPK) model for diazepam disposition investigating any loss of information using GLS and a benefit/cost criterion. As a result of the carried out investigation the initial concentration variance was preserved in the obtained lumped PBPK model.