Fuzzy simulation of pharmacokinetic models: Case study of whole body physiologically based model of diazepam

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.