Developing integrated PBPK/PD coupled mechanistic pathway model (miRNA-BDNF): An approach towards system toxicology

Abstract

Integration of a dynamic signal transduction pathway into the tissue dosimetry model is a major advancement in the area of computational toxicology. This paper illustrates the ways to incorporate the use of existing system biological model in the field of toxicology via its coupling to the Physiological based Pharmacokinetics and Pharmacodynamics (PBPK/PD) model. This expansion framework of integrated PBPK/PD coupled mechanistic system pathway model can be called as system toxicology that describes the kinetics of both - the chemicals and - biomolecules, help us to understand the dynamic and steady-state behaviors of molecular pathways under perturbed condition. The objective of this article is to illustrate a system toxicology based approach by developing an integrated PBPK/PD coupled miRNA-BDNF pathway model and to demonstrate its application by taking a case study of the PFOS mediated neurotoxicity. System dynamic involves miRNA-mediated BDNF regulation, which plays an important role in the control of neuronal cell proliferation, differentiation, and survivability.

An integrative translational framework for chemical induced neurotoxicity – a systematic review

“…They conducted epidemiological study to evaluate neurotoxicity of persistent organic pollutant in Spanish children through breastfeeding exposure to validate the results from PBPK model for postnatal exposure assessment. In addition, Sharma et al (2017) showed one example of integrated approach. Authors used PBPK/PD model to understand dynamics and steady state behavior of cellular response under perturbed condition.…”

Mechanistic Computational Models of MicroRNA-Mediated Signaling Networks in Human Diseases

“…By taking into account the clinical knowledge of various disease-related factors (e.g., let-7, Myc, and TGF-β) at the systems level, the models have proposed novel mechanisms to help explain the pathophysiology of abnormal angiogenesis in peripheral arterial disease and cancer [66,67]. In a more pharmaceutically related attempt, Sharma et al combined a physiologically based pharmacokinetic model of PFOS (perfluorooctane sulfonate) exposure with a mechanistic model of miR-mediated BDNF (brain derived neurotrophic factor) production to investigate the quantitative impacts of PFOS-induced neurotoxicity [64]. This basic model can serve as a template for more advanced quantitative systems toxicology/pharmacology (QST/QSP) studies in modern pharmaceutical research and development, especially when miRs themselves are pursued as therapeutic leads or considered as important regulators of a drug’s function and toxicity.…”

In silico models in drug development: where we are

“…Furthermore, PBPK models can be expanded by adding mechanistic models of gene regulation and signaling pathways. For instance, a PBPK model was coupled with the miRNA-BDNF pathway to study perfluorooctanesulfonic acid induced neurotoxicity [29]. In another study, Mason et al combined PK and mechanistic models to estimate the dose and time of ingestion in paracetamol poisoning, using traditional and experimental serum biomarkers in mice [30]**.…”