Challenges and Opportunities for In Vitro-In Vivo Extrapolation of Aldehyde Oxidase-Mediated Clearance : Toward a Roadmap for Quantitative Translation
Copyright © 2023 by The Author(s)..
Underestimation of aldehyde oxidase (AO)-mediated clearance by current in vitro assays leads to uncertainty in human dose projections, thereby reducing the likelihood of success in drug development. In the present study we first evaluated the current drug development practices for AO substrates. Next, the overall predictive performance of in vitro-in vivo extrapolation of unbound hepatic intrinsic clearance (CLint,u) and unbound hepatic intrinsic clearance by AO (CLint,u,AO) was assessed using a comprehensive literature database of in vitro (human cytosol/S9/hepatocytes) and in vivo (intravenous/oral) data collated for 22 AO substrates (total of 100 datapoints from multiple studies). Correction for unbound fraction in the incubation was done by experimental data or in silico predictions. The fraction metabolized by AO (fmAO) determined via in vitro/in vivo approaches was found to be highly variable. The geometric mean fold errors (gmfe) for scaled CLint,u (mL/min/kg) were 10.4 for human hepatocytes, 5.6 for human liver cytosols, and 5.0 for human liver S9, respectively. Application of these gmfe's as empirical scaling factors improved predictions (45%-57% within twofold of observed) compared with no correction (11%-27% within twofold), with the scaling factors qualified by leave-one-out cross-validation. A road map for quantitative translation was then proposed following a critical evaluation on the in vitro and clinical methodology to estimate in vivo fmAO In conclusion, the study provides the most robust system-specific empirical scaling factors to date as a pragmatic approach for the prediction of in vivo CLint,u,AO in the early stages of drug development. SIGNIFICANCE STATEMENT: Confidence remains low when predicting in vivo clearance of AO substrates using in vitro systems, leading to de-prioritization of AO substrates from the drug development pipeline to mitigate risk of unexpected and costly in vivo impact. The current study establishes a set of empirical scaling factors as a pragmatic tool to improve predictability of in vivo AO clearance. Developing clinical pharmacology strategies for AO substrates by utilizing mass balance/clinical drug-drug interaction data will help build confidence in fmAO.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:51 |
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| Enthalten in: |
Drug metabolism and disposition: the biological fate of chemicals - 51(2023), 12 vom: 26. Dez., Seite 1591-1606 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Izat, Nihan [VerfasserIn] |
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| Themen: |
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| Anmerkungen: |
Date Completed 16.11.2023 Date Revised 22.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1124/dmd.123.001436 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM362483329 |
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| 245 | 1 | 0 | |a Challenges and Opportunities for In Vitro-In Vivo Extrapolation of Aldehyde Oxidase-Mediated Clearance |b Toward a Roadmap for Quantitative Translation |
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| 520 | |a Copyright © 2023 by The Author(s). | ||
| 520 | |a Underestimation of aldehyde oxidase (AO)-mediated clearance by current in vitro assays leads to uncertainty in human dose projections, thereby reducing the likelihood of success in drug development. In the present study we first evaluated the current drug development practices for AO substrates. Next, the overall predictive performance of in vitro-in vivo extrapolation of unbound hepatic intrinsic clearance (CLint,u) and unbound hepatic intrinsic clearance by AO (CLint,u,AO) was assessed using a comprehensive literature database of in vitro (human cytosol/S9/hepatocytes) and in vivo (intravenous/oral) data collated for 22 AO substrates (total of 100 datapoints from multiple studies). Correction for unbound fraction in the incubation was done by experimental data or in silico predictions. The fraction metabolized by AO (fmAO) determined via in vitro/in vivo approaches was found to be highly variable. The geometric mean fold errors (gmfe) for scaled CLint,u (mL/min/kg) were 10.4 for human hepatocytes, 5.6 for human liver cytosols, and 5.0 for human liver S9, respectively. Application of these gmfe's as empirical scaling factors improved predictions (45%-57% within twofold of observed) compared with no correction (11%-27% within twofold), with the scaling factors qualified by leave-one-out cross-validation. A road map for quantitative translation was then proposed following a critical evaluation on the in vitro and clinical methodology to estimate in vivo fmAO In conclusion, the study provides the most robust system-specific empirical scaling factors to date as a pragmatic approach for the prediction of in vivo CLint,u,AO in the early stages of drug development. SIGNIFICANCE STATEMENT: Confidence remains low when predicting in vivo clearance of AO substrates using in vitro systems, leading to de-prioritization of AO substrates from the drug development pipeline to mitigate risk of unexpected and costly in vivo impact. The current study establishes a set of empirical scaling factors as a pragmatic tool to improve predictability of in vivo AO clearance. Developing clinical pharmacology strategies for AO substrates by utilizing mass balance/clinical drug-drug interaction data will help build confidence in fmAO | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 7 | |a EC 1.2.3.1 |2 NLM | |
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| 700 | 1 | |a Abbasi, Armina |e verfasserin |4 aut | |
| 700 | 1 | |a Cheruzel, Lionel |e verfasserin |4 aut | |
| 700 | 1 | |a Jones, Robert S |e verfasserin |4 aut | |
| 700 | 1 | |a Moss, Darren |e verfasserin |4 aut | |
| 700 | 1 | |a Ortega-Muro, Fatima |e verfasserin |4 aut | |
| 700 | 1 | |a Parmentier, Yannick |e verfasserin |4 aut | |
| 700 | 1 | |a Peterkin, Vincent C |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Dan-Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Venkatakrishnan, Karthik |e verfasserin |4 aut | |
| 700 | 1 | |a Zientek, Michael A |e verfasserin |4 aut | |
| 700 | 1 | |a Barber, Jill |e verfasserin |4 aut | |
| 700 | 1 | |a Houston, J Brian |e verfasserin |4 aut | |
| 700 | 1 | |a Galetin, Aleksandra |e verfasserin |4 aut | |
| 700 | 1 | |a Scotcher, Daniel |e verfasserin |4 aut | |
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