AUTHOR=Algharably Engi Abdelhady , Di Consiglio Emma , Testai Emanuela , Pistollato Francesca , Mielke Hans , Gundert-Remy Ursula 

TITLE=In Vitro–In Vivo Extrapolation by Physiologically Based Kinetic Modeling: Experience With Three Case Studies and Lessons Learned

JOURNAL=Frontiers in Toxicology

VOLUME=Volume 4 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2022.885843

DOI=10.3389/ftox.2022.885843

ISSN=2673-3080

ABSTRACT=Physiologically-based kinetic (PBK) modelling has been increasingly used since the beginning of the 21st century to support dose selection to be used in preclinical and clinical safety studies in the pharmaceutical sector. For chemical safety assessment, the use of PBK has also found interest, however to a smaller extent although an internationally agreed document was published already in 2010 (IPCS/WHO). Nevertheless, at that time PBK modelling was based mostly on in vivo data as the example in the IPCS/WHO document indicates. Recently, the OECD published a guidance document which set standards how to characterize, validate and report PBK models for regulatory purposes. In the past few years, we gained experience with using in vitro data for performing quantitative in vitro- in vivo extrapolation (QIVIVE) in which biokinetic data play a crucial role to obtain a realistic estimation of human exposure. In addition, pharmaco-/toxicodynamics aspects have been introduced into the approach. Here, three examples with different drugs/chemicals are described in which different approaches have been applied. The lessons we learned from the exercise are: (1) In vitro conditions should be considered and compared to the in vivo situation, particularly, for protein binding; (2) In vitro inhibition of the metabolizing enzymes by the formed metabolites should to be taken into consideration; (3) It is important to extrapolate from the in vitro measured intracellular and not from the nominal concentration to the tissue/organ concentration to come up with an appropriate QIVIVE for the relevant adverse effects.