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

• DOI: 10.3389/ftox.2022.885843
• Publication Date: 2022-07-18T08:26:00Z
• Authors: Engi Abdelhady Al...; Emma Di Consiglio; Emanuela Testai; Francesca Pistollato; Hans Mielke; Ursula Gundert-Remy
• Keywords: reverse dosimetry; 0303 health sciences; 03 medical and health sciences; RA1190-1270; toxicokinetics; Toxicology. Poisons; risk assessment; toxicodynamics; new approach methodologies (NAMs); Toxicology; 3. Good health

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