title: Modeling bioavailability to organs protected by biological barriers.
abstract: Computational pharmacokinetic (PK) modeling gives access to drug concentration vs. time profiles in target organs and allows better interpretation of clinical observations of therapeutic or toxic effects. Physiologically-based PK (PBPK) models in particular, based on mechanistic descriptions of the body anatomy and physiology, may also help to extrapolate in vitro or animal data to human. Once in the systemic circulation, a chemical has access to the microvasculature of every organ or tissue. However, its penetration in the brain, retina, thymus, spinal cord, testis, placenta,… may be limited or even fully prevented by dynamic physiological blood-tissue barriers. Those barriers are both physical (involving tight junctions between adjacent cells) and biochemical (involving metabolizing enzymes and transporters). On those cases, correct mechanistic characterization of the passage (or not) of molecules through the barrier can be crucial for improved PBPK modeling and prediction. In parallel, attempts to understand and quantitatively characterize the processes involved in drug penetration of physiological barriers have led to the development of several in vitro experimental models. Data from such assays are very useful to calibrate PBPK models. We review here those in vitro and computational models, highlighting the challenges and perspectives for in vitro and computational models to better assess drug availability to target tissues.
authors.affiliation: Bioengineering Department, Chair of Mathematical Modeling for Systems Toxicology, Université de Technologie de Compiègne, Royallieu Research Center, Compiègne, 60200 France ; LA-SER, Strategy and Decision Analytics, 10 place de la Catalogne, Paris, 75014 France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Quignot
keywords: Bioavailability; Biological barriers; Computational model; PBPK modeling; Pharmacokinetics