Current PBPK Models: Are They Predicting Tissue Drug Concentration Correctly?
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COMMENTARY
Current PBPK Models: Are They Predicting Tissue Drug Concentration Correctly? Manuel Ibarra1 · Marta Vázquez1 · Pietro Fagiolino1 Accepted: 4 October 2020 © The Author(s) 2020
Physiologically based pharmacokinetic (PBPK) models have been receiving extensive attention from biomedical scientific journals for the last 15 years. Even though the concept was first introduced by Teorell [1], recent improvements in computing power have led to an explosive development and implementation of several software platforms containing such models at their core [2–5]. These tools are being increasingly implemented in drug discovery and development, as both the industry and the regulating agencies embrace their application for specific assessments such as drug–drug interactions and dosage recommendations in specific sub-populations [6, 7]. The reason for such interest is that PBPK models have been established as valid tools in the instrumentation of “bottom-up” and “middle-out” approaches, where the pharmacokinetic profile of a compound for a non-explored scenario can be simulated using previous knowledge of the drug and the organism, eventually integrating in-vitro experiments. This allows prior evaluation of several factors that can affect drug pharmacokinetics such as the dosage form, administration route, food intake, and comedication, and individual characteristics such as ethnicity, age, sex, and disease state [8]. Parameter optimization in PBPK modeling is routinely carried out by the adjustment of simulated concentrations to the experimental blood or plasma concentration–time profiles. Commonly, drug blood concentrations displayed in these platforms belong to both the central vein and the artery but not to peripheral veins, which are the usual sampling site in clinical trials. Several researchers became aware of this aspect and proposed some modifications to the model for the purpose of estimating the correct arteriovenous difference of drug concentrations [9–11]. * Pietro Fagiolino [email protected] 1
Pharmaceutical Sciences Department, Faculty of Chemistry, Universidad de la República, P.O.Box 1157, 11800 Montevideo, Uruguay
Nevertheless, the most important concentration to be assessed in silico, and then correlated with the in vivo profile, should be the extravascular concentration, at the site where most drugs will be acting to produce either therapeutic or toxic effects. These sites could be located in the interstitial space (external face of the cell membrane) or in the intracellular space. Hence, a better pharmacokinetic/pharmacodynamic relationship could be attained from concentrations at the action sites and not from peripheral veins. In fact, this should be the main goal for such PBPK modeling: to predict effective and safe treatments and not to forecast plasma drug concentrations anywhere along the circulatory system. Unfortunately, even though great efforts have been made to predict extravascular tissue drug concentrations using perfusion and permeability rate-limited models with appropriate ti
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