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Next Generation Risk Assessment of the Anti-Androgen Flutamide Including the Contribution of Its Active Metabolite Hydroxyflutamide

In next generation risk assessment (NGRA), non-animal approaches are used to quantify the chemical concentrations required to trigger bioactivity responses, in order to assure safe levels of human exposure. A limitation of many in vitro bioactivity assays, which are used in an NGRA context as new ap...

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Autores principales: van Tongeren, Tessa C.A., Carmichael, Paul L., Rietjens, Ivonne M.C.M., Li, Hequn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9201820/
https://www.ncbi.nlm.nih.gov/pubmed/35722059
http://dx.doi.org/10.3389/ftox.2022.881235
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author van Tongeren, Tessa C.A.
Carmichael, Paul L.
Rietjens, Ivonne M.C.M.
Li, Hequn
author_facet van Tongeren, Tessa C.A.
Carmichael, Paul L.
Rietjens, Ivonne M.C.M.
Li, Hequn
author_sort van Tongeren, Tessa C.A.
collection PubMed
description In next generation risk assessment (NGRA), non-animal approaches are used to quantify the chemical concentrations required to trigger bioactivity responses, in order to assure safe levels of human exposure. A limitation of many in vitro bioactivity assays, which are used in an NGRA context as new approach methodologies (NAMs), is that toxicokinetics, including biotransformation, are not adequately captured. The present study aimed to include, as a proof of principle, the bioactivity of the metabolite hydroxyflutamide (HF) in an NGRA approach to evaluate the safety of the anti-androgen flutamide (FLU), using the AR-CALUX assay to derive the NAM point of departure (PoD). The NGRA approach applied also included PBK modelling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE). The PBK model describing FLU and HF kinetics in humans was developed using GastroPlus™ and validated against human pharmacokinetic data. PBK model-facilitated QIVIVE was performed to translate the in vitro AR-CALUX derived concentration-response data to a corresponding in vivo dose-response curve for the anti-androgenicity of FLU, excluding and including the activity of HF (-HF and +HF, respectively). The in vivo benchmark dose 5% lower confidence limits (BMDL(05)) derived from the predicted in vivo dose-response curves for FLU, revealed a 440-fold lower BMDL(05) when taking the bioactivity of HF into account. Subsequent comparison of the predicted BMDL(05) values to the human therapeutic doses and historical animal derived PoDs, revealed that PBK modelling-facilitated QIVIVE that includes the bioactivity of the active metabolite is protective and provides a more appropriate PoD to assure human safety via NGRA, whereas excluding this would potentially result in an underestimation of the risk of FLU exposure in humans.
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spelling pubmed-92018202022-06-17 Next Generation Risk Assessment of the Anti-Androgen Flutamide Including the Contribution of Its Active Metabolite Hydroxyflutamide van Tongeren, Tessa C.A. Carmichael, Paul L. Rietjens, Ivonne M.C.M. Li, Hequn Front Toxicol Toxicology In next generation risk assessment (NGRA), non-animal approaches are used to quantify the chemical concentrations required to trigger bioactivity responses, in order to assure safe levels of human exposure. A limitation of many in vitro bioactivity assays, which are used in an NGRA context as new approach methodologies (NAMs), is that toxicokinetics, including biotransformation, are not adequately captured. The present study aimed to include, as a proof of principle, the bioactivity of the metabolite hydroxyflutamide (HF) in an NGRA approach to evaluate the safety of the anti-androgen flutamide (FLU), using the AR-CALUX assay to derive the NAM point of departure (PoD). The NGRA approach applied also included PBK modelling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE). The PBK model describing FLU and HF kinetics in humans was developed using GastroPlus™ and validated against human pharmacokinetic data. PBK model-facilitated QIVIVE was performed to translate the in vitro AR-CALUX derived concentration-response data to a corresponding in vivo dose-response curve for the anti-androgenicity of FLU, excluding and including the activity of HF (-HF and +HF, respectively). The in vivo benchmark dose 5% lower confidence limits (BMDL(05)) derived from the predicted in vivo dose-response curves for FLU, revealed a 440-fold lower BMDL(05) when taking the bioactivity of HF into account. Subsequent comparison of the predicted BMDL(05) values to the human therapeutic doses and historical animal derived PoDs, revealed that PBK modelling-facilitated QIVIVE that includes the bioactivity of the active metabolite is protective and provides a more appropriate PoD to assure human safety via NGRA, whereas excluding this would potentially result in an underestimation of the risk of FLU exposure in humans. Frontiers Media S.A. 2022-06-02 /pmc/articles/PMC9201820/ /pubmed/35722059 http://dx.doi.org/10.3389/ftox.2022.881235 Text en Copyright © 2022 van Tongeren, Carmichael, Rietjens and Li. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Toxicology
van Tongeren, Tessa C.A.
Carmichael, Paul L.
Rietjens, Ivonne M.C.M.
Li, Hequn
Next Generation Risk Assessment of the Anti-Androgen Flutamide Including the Contribution of Its Active Metabolite Hydroxyflutamide
title Next Generation Risk Assessment of the Anti-Androgen Flutamide Including the Contribution of Its Active Metabolite Hydroxyflutamide
title_full Next Generation Risk Assessment of the Anti-Androgen Flutamide Including the Contribution of Its Active Metabolite Hydroxyflutamide
title_fullStr Next Generation Risk Assessment of the Anti-Androgen Flutamide Including the Contribution of Its Active Metabolite Hydroxyflutamide
title_full_unstemmed Next Generation Risk Assessment of the Anti-Androgen Flutamide Including the Contribution of Its Active Metabolite Hydroxyflutamide
title_short Next Generation Risk Assessment of the Anti-Androgen Flutamide Including the Contribution of Its Active Metabolite Hydroxyflutamide
title_sort next generation risk assessment of the anti-androgen flutamide including the contribution of its active metabolite hydroxyflutamide
topic Toxicology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9201820/
https://www.ncbi.nlm.nih.gov/pubmed/35722059
http://dx.doi.org/10.3389/ftox.2022.881235
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