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.

Different expression of β subunits of the KCa1.1 channel by invasive and non-invasive human fibroblast-like synoviocytes

“…The incidence of RA is higher in women than in men [ 1 – 3 ]; in the majority of patients, there would therefore not be a concern about male reproductive organ toxicity. Furthermore, the testes are protected by the blood-testis barrier that prevents access by many drugs [ 59 ]. It is therefore possible to design KCa1.1 blockers that cannot cross this barrier.…”

Computational pharmacokinetics at a crossroads

“…It also illustrates one of the most important and sought for application of PBPK modeling Adler et al ( 2011 ): Quantitative in vitro to in vivo extrapolation (QIVIVE). This is also a topic of the review paper by N. Quignot Quignot, ( 2013 , in the context of blood to tissue barriers, and of the last paper from A. Owen's group Siccardi et al ( 2013 ). Quignot's paper actually returns us back at some foundational issues in PBPK modeling.…”

Physiologically Based Pharmacokinetic Modeling of Nanoparticles

“…Permeability-limited models consider tissue cell membranes as diffusional barriers to the studied drug, and the tissue cell membranes divide the tissue into intracellular space and extracellular space. 16,37 Active drug transporters on cell membranes could also be modeled by incorporating uptake/efflux transporting mechanisms. 16,37 The model parameters associated with uptake/efflux transporters, like affinity and capacity, are usually derived from cell-based assays and are often adjusted using empirical in vitro - in vivo extrapolation (IVIVE) approaches.…”

“…16 The drug-specific parameters are frequently scaled from a variety of in vitro systems. 16,37 For instance, drug clearance from the liver can be scaled based on in vitro measurements using recombinant enzymes, liver microsomes, or hepatocytes. 16,17 The drug-specific k p , which is defined by the tissue/blood concentration ratios at steady state, can be estimated using in silico methods based on both tissue composition and drug physicochemical characteristics, such as lipophilicity, charge, and protein binding.…”