Journal article
Integrating in vitro testing and physiologically-based pharmacokinetic (PBPK) modelling for chemical liver toxicity assessment—A case study of troglitazone
Environmental toxicology and pharmacology, Vol.74, pp.103296-103296
02/2020
DOI: 10.1016/j.etap.2019.103296
PMID: 31783317
Abstract
•A PBPK model was developed to predicting pharmacokinetics of troglitazone in human.•Mitochondria-mediated toxicity endpoints were used to derive BMDLs.•The performance of the animal-free approach was preliminarily evaluated in human.•The BMDLs based Cmax metric matched well with clinical hepatotoxic context.
In vitro to in vivo extrapolation (IVIVE) for next-generation risk assessment (NGRA) of chemicals requires computational modeling and faces unique challenges. Using mitochondria-related toxicity data of troglitazone (TGZ), a prototype drug known for liver toxicity, from HepaRG, HepG2, HC-04, and primary human hepatocytes, we explored inherent uncertainties in IVIVE, including cell models, cellular response endpoints, and dose metrics. A human population physiologically-based pharmacokinetic (PBPK) model for TGZ was developed to predict in vivo doses from in vitro point-of-departure (POD) concentrations. Compared to the 200–800 mg/d dose range of TGZ where liver injury was observed clinically, the predicted POD doses for the mean and top one percentile of the PBPK population were 28–372 and 15–178 mg/d respectively based on Cmax dosimetry, and 185–2552 and 83–1010 mg/d respectively based on AUC. In conclusion, although with many uncertainties, integrating in vitro assays and PBPK modeling is promising in informing liver toxicity-inducing TGZ doses.
Details
- Title: Subtitle
- Integrating in vitro testing and physiologically-based pharmacokinetic (PBPK) modelling for chemical liver toxicity assessment—A case study of troglitazone
- Creators
- Lin Yu - Academy of Military ScienceHequn Li - UnileverChi Zhang - Academy of Military ScienceQiang Zhang - Emory UniversityJiabin Guo - Chinese Center For Disease Control and PreventionJin LiHaitao Yuan - Chinese Center For Disease Control and PreventionLizhong Li - Chinese Center For Disease Control and PreventionPaul Carmichael - UnileverShuangqing Peng - Chinese Center For Disease Control and Prevention
- Resource Type
- Journal article
- Publication Details
- Environmental toxicology and pharmacology, Vol.74, pp.103296-103296
- Publisher
- Elsevier B.V
- DOI
- 10.1016/j.etap.2019.103296
- PMID
- 31783317
- ISSN
- 1382-6689
- eISSN
- 1872-7077
- Grant note
- DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 81430090, 81470167; DOI: 10.13039/501100005090, name: Beijing Nova Program, award: Z171100001117103; name: AMMS Innovative Foundation, award: 2017CXJJ13; name: Unilever International Collaborative, award: MA-2015-00410
- Language
- English
- Date published
- 02/2020
- Academic Unit
- Neurology
- Record Identifier
- 9984303027602771
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