Journal article
Next generation risk assessment (NGRA): Bridging in vitro points-of-departure to human safety assessment using physiologically-based kinetic (PBK) modelling ? A case study of doxorubicin with dose metrics considerations
Toxicology in vitro, Vol.74, pp.105171-105171
08/01/2021
DOI: 10.1016/j.tiv.2021.105171
PMID: 33848589
Abstract
Using the chemical doxorubicin (DOX), the objective of the present study was to evaluate the impact of dose metrics selection in the new approach method of integrating physiologically-based kinetic (PBK) modelling and relevant human cell-based assays to inform a priori the point of departure for human health risk. We reviewed the literature on the clinical consequences of DOX treatment to identify dosing scenarios with no or mild cardiotoxicity observed. Key concentrations of DOX that induced cardiomyocyte toxicity in vitro were derived from studies of our own and others. A human population-based PBK model of DOX was developed and verified against pharmacokinetic data. The model was then used to predict plasma and extracellular and intracellular heart concentrations of DOX under selected clinical settings and compared with in vitro outcomes, based on several dose metrics: Cmax (maximum concentration) or AUC (area under concentration-time curve) in free or total form of DOX. We found when using in vitro assays to predict cardiotoxicity for DOX, AUC is a better indicator. Our study illustrates that when appropriate dose metrics are used, it is possible to combine PBK modelling with in vitro-derived toxicity information to define margins of safety and predict low-risk human exposure levels.
Details
- Title: Subtitle
- Next generation risk assessment (NGRA): Bridging in vitro points-of-departure to human safety assessment using physiologically-based kinetic (PBK) modelling ? A case study of doxorubicin with dose metrics considerations
- Creators
- Hequn Li - UnileverHaitao Yuan - Academy of Military Medical SciencesAlistair Middleton - UnileverJin LiBeate Nicol - UnileverPaul Carmichael - UnileverJiabin Guo - Academy of Military Medical SciencesShuangqing Peng - Academy of Military Medical SciencesQiang Zhang - Emory University
- Resource Type
- Journal article
- Publication Details
- Toxicology in vitro, Vol.74, pp.105171-105171
- Publisher
- Elsevier
- DOI
- 10.1016/j.tiv.2021.105171
- PMID
- 33848589
- ISSN
- 0887-2333
- eISSN
- 1879-3177
- Number of pages
- 12
- Grant note
- MA201502026 / UnileverEmory Collaborative Project; Unilever 81430090 / National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) MA-2015-00410 / Unilever International Collaborative Project; Unilever
- Language
- English
- Date published
- 08/01/2021
- Academic Unit
- Neurology
- Record Identifier
- 9984302214702771
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