Barira Islam is a Senior Research Scientist in Quantitative Systems Toxicology and Safety (QSTS) division of Simcyp, Certara UK. She is a chemist by training and joined Certara in April 2021. Barira holds a Ph.D. in Biotechnology from Aligarh Muslim University, India. She then moved to the UK and worked as a postdoc on various projects in molecular modelling and simulations. Within Simcyp, sheworks on interdisciplinary projects of mechanistic modelling and safety pharmacology analysis of the
drugs.
OpenTox 2022 Virtual Conference
Use of biokinetic and PBPK modelling for toxicological assessment by NAMs
The in vitro approach for hazard assessment of compounds involves evaluating the potential of compounds to cause a biological event that can lead to toxicity. In the EUToxrisk project, we tested New Approach Methods (NAMs) by combining in vitro toolbox with biokinetic and physiological-based pharmacokinetic (PBPK) modelling to predict toxicological doses of the compounds. In this regard, nominal effect concentrations from in vitro toxicity assays may lead to inaccurate estimations of in vivo toxic doses because the nominal concentration poorly reflects the concentration at the molecular target in cells in vitro, which is responsible for initiating effects and can be referred to as the biologically effective dose. Compounds can differentially distribute between in vitro assay compartments as they can bind to microtiter plate plastic, serum constituents in exposure medium, and cellular components and distribute into head space. Biokinetic modelling considers the distribution of compounds into these compartments and can predict free concentration in the medium which is considered better proxies of the biologically effective doses.
The predicted biologically effective doses can be compared to the concentrations achieved in vivo by in vitro in vivo extrapolations (IVIVE) carried out using PBPK modelling. PBPK modelling can predict the plasma and tissue concentrations of compound over time in a particular population following a particular route of exposure. PBPK models are constructed using a series of differential equations that are parameterized with known physiological variables and represent a quantitative mechanistic framework by which the absorption, distribution, metabolism, and excretion (ADME) of compounds can be described. I will discuss background and parameter requirements for biokinetic and PBPK modelling in Simcyp and how these can be useful for the risk assessment of compounds.