Fuzzy Simulation of Pharmacokinetic Models: Case Study of Whole Body Physiologically Based Model of Diazepam |
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Authors: | Ivelina I. Gueorguieva Ivan A. Nestorov Malcolm Rowland |
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Affiliation: | Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK. ivelina.gueorguieva@man.ac.uk |
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Abstract: | The aim of the present study is to develop and implement a methodology that accounts for parameter variability and uncertainty in the presence of qualitative and semi-quantitative information (fuzzy simulations) as well as when some parameters are better quantitatively defined than others (fuzzy-probabilistic approach). The fuzzy simulations method consists of (i) representing parameter uncertainty and variability by fuzzy numbers and (ii) simulating predictions by solving the pharmacokinetic model. The fuzzy-probabilistic approach includes an additional transformation between fuzzy numbers and probability density functions. To illustrate the proposed method a diazepam WBPBPK model was used where the information for hepatic intrinsic clearance determined by in vitro-in vivo scaling was semi-quantitative. The predicted concentration time profiles were compared with those resulting from a Monte Carlo simulation. Fuzzy simulations can be used as an alternative to Monte Carlo simulation. |
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Keywords: | prediction variability uncertainty fuzzy simulation fuzzy-probabilistic Monte Carlo simulation whole body physiologically based pharmacokinetic model diazepam parameter estimation |
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