title: Fuzzy simulation of pharmacokinetic models: case study of whole body physiologically based model of diazepam.
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.
authors.affiliation: Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, UK. ivelina.gueorguieva@man.ac.uk
authors.forename: Ivelina I
authors.initials: II
authors.lastname: Gueorguieva
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Nestorov
authors.forename: Malcolm
authors.initials: M
authors.lastname: Rowland
mesh_terms: D000818:Animals; D003975:Diazepam / Q000493:pharmacokinetics*; D017143:Fuzzy Logic; D008297:Male; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003975:Diazepam