PopGen: simulatore della popolazione umana nella farmacologia

[McNally K, Cotton R, Hogg A, Loizou G. PopGen: A virtual human population generator. Toxicology. 2014 Jan 6;315:70-85.]


The risk assessment of environmental chemicals and drugs is moving towards a paradigm shift in approach which seeks the full replacement animal testing with high throughput, mechanistic, in vitro systems. This new vision will be reliant on the measurement in vitro, of concentration-dependent responses where prolonged excessive perturbations of specific biochemical pathways are likely to lead to adverse health effects in an intact organism. Such an approach requires a framework, into which disparate data generated using in vitro, in silico and in chemico systems, can be integrated and utilised for quantitative in vitro-to-in vivo extrapolation (QIVIVE), ultimately to the human population level. Physiologically based pharmacokinetic (PBPK) models are ideally suited for this and are obligatory in order to translate in vitro concentration-response relationships to an exposure or dose, route and duration regime in people. In this report we describe PopGen, a virtual human population generator which is a user friendly, open access web-based application for the prediction of realistic anatomical, physiological and phase 1 metabolic variation in a wide range of healthy human populations. We demonstrate how PopGen can be used for QIVIVE by providing input to a PBPK model, at an appropriate level of detail, to reconstruct exposure from human biomonitoring data. We discuss how the process of exposure reconstruction from blood biomarkers, in general, is analogous to exposure or dose reconstruction from concentration-response measurements made in proposed in vitro cell based systems which are assumed to be surrogates for target organs.


[Willmann S, Höhn K, Edginton A, Sevestre M, Solodenko J, Weiss W, Lippert J, Schmitt W. Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs. J Pharmacokinet Pharmacodyn. 2007 Jun;34(3):401-31.]


In clinical development stages, an a priori assessment of the sensitivity of the pharmacokinetic behavior with respect to physiological and anthropometric properties of human (sub-) populations is desirable. A physiology-based pharmacokinetic (PBPK) population model was developed that makes use of known distributions of physiological and anthropometric properties obtained from the literature for realistic populations. As input parameters, the simulation model requires race, gender, age, and two parameters out of body weight, height and body mass index. From this data, the parameters relevant for PBPK modeling such as organ volumes and blood flows are determined for each virtual individual. The resulting parameters were compared to those derived using a previously published model (P(3)M). Mean organ weights and blood flows were highly correlated between the two models, despite the different methods used to generate these parameters. The inter-individual variability differed greatly especially for organs with a log-normal weight distribution (such as fat and spleen). Two exemplary population pharmacokinetic simulations using ciprofloxacin and paclitaxel as model drugs showed good correlation to observed variability. A sensitivity analysis demonstrated that the physiological differences in the virtual individuals and intrinsic clearance variability were equally influential to the pharmacokinetic variability but were not additive. In conclusion, the new population model is well suited to assess the influence of individual physiological variability on the pharmacokinetics of drugs. It is expected that this new tool can be beneficially applied in the planning of clinical studies.



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