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Simcyp Animal Simulator
Models within the Simcyp Simulator allow for the in silico prediction of drug kinetics in virtual animals. Currently dog, rat and knock-out mouse models have been integrated into the Population-based Simulator – these are also available as standalone modules.
Key features of the Simcyp Animal Simulators include:
Simcyp Dog, Rat and Mouse use WBPBPK modelling to predict the pharmacokinetic behaviour of a compound in these animals. Making use of tissue volumes, blood flows, tissue compositions and other physiological parameters in conjunction with in vitro experimental data allows the kinetics of a drug to be predicted. Users can select one of three administration routes – iv bolus, iv infusion or oral.
The advanced dissolution, absorption and metabolism (ADAM) model is a physiological model for drug absorption and metabolism in the gastrointestinal tract. This model takes account of physiological factors (e.g. gastrointestinal residence time, fluid dynamics, regional pH values, regional gut metabolism, food effects), physicochemical characteristics (e.g. solubility, permeability), and formulation factors (e.g. modified release dosage forms, particle size). It allows simulations to be performed in either fasted or fed states. Additional features in Simcyp Dog and Mouse include a mechanistic model of gut wall permeability. There is also the ability to incorporate inter-individual variability into dog simulations.
Prediction of clearance
In vivo hepatic clearance and first-pass gut metabolism can be extrapolated from data generated from commonly used in vitro systems.
Prediction of distribution
Tissue-plasma partition coefficients (Kp values) and volume of distribution can be predicted by two commonly used methods: Poulin & Theil (corrected by Berezhkovskiy) and Rodgers & Rowland.
Simcyp Animal has the capacity to model both the formation of a metabolite from its parent compound and its kinetics. It is particularly advantageous when the metabolite is active or reactive. The metabolite formation in the gut and liver are both accommodated.
A unique feature of the Simcyp Mouse model is the ability to create virtual transgenic mice by adding (knocking-in) or deleting (knocking-out) certain genes controlling drug metabolising enzymes and transporters.
Automated data import from Excel
A tool for automated compound data import from Excel has been developed. This tool facilitates handling of large numbers of compounds.
Batch processing and automated sensitivity analysis (ASA)
In line with the Population-based Simulator, Simcyp Animal provides tools to run large numbers of simulations in batch mode (e.g. overnight). Automated sensitivity analysis can be applied to up to two parameters simultaneously with graphical output of a large number of user-defined endpoints (e.g. AUC, fa, Vss, CLiv, CLpo, Cmax etc).
Figure 15 Predicted vs observed Vss (volume of distribution at steady state) in rat for 11 compounds. P&T: Poulin and Theil; R&R: Rodgers & Rowland.