PBPK modeling to evaluate maximum tolerated doses: A case study with 3-chloroallyl alcohol
Introduction: A physiologically based pharmacokinetic (PBPK) model for 3-chloroallyl alcohol (3-CAA) was developed and used to evaluate the design of assays for the in vivo genotoxicity of 3-CAA.Methods: Model development was supported by read across from a published PBPK model for ethanol. Read acr...
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| Format: | Article |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1088011/full |
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| author | Rory P. Conolly Harvey J. Clewell Martha M. Moore Jerry L. Campbell Wanyun Cheng R. Robinan Gentry |
| author_facet | Rory P. Conolly Harvey J. Clewell Martha M. Moore Jerry L. Campbell Wanyun Cheng R. Robinan Gentry |
| author_sort | Rory P. Conolly |
| collection | DOAJ |
| description | Introduction: A physiologically based pharmacokinetic (PBPK) model for 3-chloroallyl alcohol (3-CAA) was developed and used to evaluate the design of assays for the in vivo genotoxicity of 3-CAA.Methods: Model development was supported by read across from a published PBPK model for ethanol. Read across was motivated by the expectation that 3-CAA, which like ethanol is a primary alcohol, is metabolized largely by hepatic alcohol dehydrogenases. The PBPK model was used to evaluate how two metrics of tissue dosimetry, maximum blood concentration (Cmax; mg/L) and area under the curve (AUC; mg-hr/L) vary with dose of 3-CAA and with dose route (oral gavage, drinking water).Results: The model predicted that oral gavage results in a 6-fold higher Cmax than the same dose administered in drinking water, but in similar AUCs. Predicted Cmax provided the best correlation with severe toxicity (e.g., lethality) from 3-CAA, consistent with the production of a reactive metabolite. Therefore, drinking water administration can achieve higher sustained concentration without severe toxicity in vivo.Discussion: This evaluation is significant because cytotoxicity is a potential confounder of mutagenicity testing. The PBPK model can be used to ensure that studies meet OECD and USEPA test guidelines and that the highest dose used is not associated with severe toxicity. In addition, PBPK modeling provides assurance of target tissue (e.g., bone marrow) exposure even in the absence of laboratory data, by defining the relationship between applied dose and target tissue dose based on accepted principles of pharmacokinetics, relevant physiology and biochemistry of the dosed animals, and chemical-specific information. |
| first_indexed | 2024-04-10T08:48:27Z |
| format | Article |
| id | doaj.art-d8f7461641fa4ee682ebb9ff72cdf343 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-10T08:48:27Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-d8f7461641fa4ee682ebb9ff72cdf3432023-02-22T04:57:25ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-02-011410.3389/fphar.2023.10880111088011PBPK modeling to evaluate maximum tolerated doses: A case study with 3-chloroallyl alcoholRory P. Conolly0Harvey J. Clewell1Martha M. Moore2Jerry L. Campbell3Wanyun Cheng4R. Robinan Gentry5Ramboll US Corporation, Monroe, LA, United StatesRamboll US Corporation, Monroe, LA, United StatesMartha M. Moore LLC, Little Rock, AR, United StatesRamboll US Corporation, Monroe, LA, United StatesUPL Limited, Inc, Durham, NC, United StatesRamboll US Corporation, Monroe, LA, United StatesIntroduction: A physiologically based pharmacokinetic (PBPK) model for 3-chloroallyl alcohol (3-CAA) was developed and used to evaluate the design of assays for the in vivo genotoxicity of 3-CAA.Methods: Model development was supported by read across from a published PBPK model for ethanol. Read across was motivated by the expectation that 3-CAA, which like ethanol is a primary alcohol, is metabolized largely by hepatic alcohol dehydrogenases. The PBPK model was used to evaluate how two metrics of tissue dosimetry, maximum blood concentration (Cmax; mg/L) and area under the curve (AUC; mg-hr/L) vary with dose of 3-CAA and with dose route (oral gavage, drinking water).Results: The model predicted that oral gavage results in a 6-fold higher Cmax than the same dose administered in drinking water, but in similar AUCs. Predicted Cmax provided the best correlation with severe toxicity (e.g., lethality) from 3-CAA, consistent with the production of a reactive metabolite. Therefore, drinking water administration can achieve higher sustained concentration without severe toxicity in vivo.Discussion: This evaluation is significant because cytotoxicity is a potential confounder of mutagenicity testing. The PBPK model can be used to ensure that studies meet OECD and USEPA test guidelines and that the highest dose used is not associated with severe toxicity. In addition, PBPK modeling provides assurance of target tissue (e.g., bone marrow) exposure even in the absence of laboratory data, by defining the relationship between applied dose and target tissue dose based on accepted principles of pharmacokinetics, relevant physiology and biochemistry of the dosed animals, and chemical-specific information.https://www.frontiersin.org/articles/10.3389/fphar.2023.1088011/fullPBPKMTDgenotoxicityreduction3-chloroallyl alcohol |
| spellingShingle | Rory P. Conolly Harvey J. Clewell Martha M. Moore Jerry L. Campbell Wanyun Cheng R. Robinan Gentry PBPK modeling to evaluate maximum tolerated doses: A case study with 3-chloroallyl alcohol Frontiers in Pharmacology PBPK MTD genotoxicity reduction 3-chloroallyl alcohol |
| title | PBPK modeling to evaluate maximum tolerated doses: A case study with 3-chloroallyl alcohol |
| title_full | PBPK modeling to evaluate maximum tolerated doses: A case study with 3-chloroallyl alcohol |
| title_fullStr | PBPK modeling to evaluate maximum tolerated doses: A case study with 3-chloroallyl alcohol |
| title_full_unstemmed | PBPK modeling to evaluate maximum tolerated doses: A case study with 3-chloroallyl alcohol |
| title_short | PBPK modeling to evaluate maximum tolerated doses: A case study with 3-chloroallyl alcohol |
| title_sort | pbpk modeling to evaluate maximum tolerated doses a case study with 3 chloroallyl alcohol |
| topic | PBPK MTD genotoxicity reduction 3-chloroallyl alcohol |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1088011/full |
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