Pharmacological Treatment of TBI

Traumatic Brain Injury (TBI) is a leading cause of death and disability and presents a significant socioeconomic challenge. Exposure to blast waves, motor vehicle accidents, falls and violence account for 2M TBI cases with a death rate estimated at ~52000 per year. Health care costs associated with TBI is about $60B despite intense efforts to minimize it. The pathology associated with TBI is complex and time dependent and is classified into primary and secondary injury. Primary injury is associated with initial mechanical insult and can be diffuse, focal or multifocal. It triggers a complex cascade of biochemical events called secondary or delayed injury that can occur for hours, days and even weeks. Secondary injury results in delayed tissue damage and provides a “window of opportunity” for pharmacological intervention and treatment.

The secondary brain injury mechanisms start immediately after the primary insult and, depending on the injury severity, last for long period of time –for minutes-hours-days-months. Vast cascade of brain injury mechanisms involve physiological, neurobiological and psychological complications such as depression, memory loss, sleep disorders, epilepsy, and others.

CFDRC is developing multiscale modeling tools, “Leonardo”, for integrated “top-down” whole body physiology based pharmacokinetics (PBPK) and “bottom-up” systems biology based pharmacodynamics (PD) and toxicology. The pharmacokinetics module accounts for drug administration, distribution among various organs partitioning into tissue interstitium and cellular spaces, metabolism and excretion (ADME). Biochemical reaction mechanisms are constructed to simulate drug interaction with plasma proteins, drug binding to plasma cells, endothelial cells, as well as passive and facilitated transport across the endothelial and epithelial barriers. The PK module provides the “initial conditions” for the PD module. The pharmacodynamics module is essentially a cell systems biology modeling tool that simulates drug interaction with intracellular signaling and metabolic pathways. It interacts with the PK model to calculate drug metabolism rates, rate of metabolite formation, and with the physiology model by changing the membrane and tissue physical properties (e.g. vasodilation, vascular permeability, tissue perfusion, etc.), biological processes (metabolic pathways, release and modulation of immune cytokines, oxidative stress, apoptosis, and physiological properties (e.g. heart rate or other autoregulation responses). For instance, in the case of TBI induced secondary damage, the PD model accounts for drug interaction at pharmacological targets within the therapeutic window, quantify dose-response relationship and predict treatment efficacy.

Pharmacological Treatment of TBI