SimRFlow: An R-based workflow for automated high-throughput PBPK simulation with the Simcyp^® simulator

SimRFlow is a high-throughput physiologically based pharmacokinetic (PBPK) modelling tool which uses Certara's Simcyp® simulator. The workflow is comprised of three main modules: 1) a Data Collection module for automated curation of physicochemical (from ChEMBL and the Norman Suspect List databases) and experimental data (i.e.: clearance, plasma-protein binding, and blood-to-plasma ratio, from httk-R package databases), 2) a Simulation module which activates the Simcyp® simulator and runs Monte Carlo simulations on virtual subjects using the curated data, and 3) a Data Visualisation module for understanding the simulated compound-specific profiles and predictions. SimRFlow has three administration routes (oral, intravenous, dermal) and allows users to change some simulation parameters including the number of subjects, simulation duration, and dosing. Users are only expected to provide a file of the compounds they wish to simulate, and in return the workflow provides summary statistics, concentration-time profiles of various tissue types, and a database file (containing in-depth results) for each simulated compound. This is presented within a guided and easy-to-use R Shiny interface which provides many plotting options for the visualisation of concentration-time profiles, parameter distributions, trends between the different parameters, as well as comparison of predicted parameters across all batch-simulated compounds. The in-built R functions can be assembled in user-customised scripts which allows for the modification of the workflow for different purposes. SimRFlow proves to be a time-efficient tool for simulating a large number of compounds without any manual curation of physicochemical or experimental data necessary to run Simcyp® simulations.