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A Cocktail Interaction Study Evaluating the Drug‐Drug Interaction Potential of the Perpetrator Drug ASP8477 at Multiple Ascending Dose Levels

ASP8477 (molecular weight 325.36 g/mol) is a fatty acid amide hydrolase inhibitor intended for the treatment of neuropathic pain. Results from in vitro studies indicated that ASP8477 is a direct inhibitor of cytochrome P450 (CYP) 2C8, 2C9, 2C19, 2D6, and 3A4 enzymes at expected efficacious concentra...

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Autores principales: Treijtel, Nicoline, Collins, Christiane, van Bruijnsvoort, Michel, Fuhr, Rainard, Ernault, Etienne, Gangaram‐Panday, Shanti, Passier, Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593727/
https://www.ncbi.nlm.nih.gov/pubmed/30730615
http://dx.doi.org/10.1002/cpdd.660
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author Treijtel, Nicoline
Collins, Christiane
van Bruijnsvoort, Michel
Fuhr, Rainard
Ernault, Etienne
Gangaram‐Panday, Shanti
Passier, Paul
author_facet Treijtel, Nicoline
Collins, Christiane
van Bruijnsvoort, Michel
Fuhr, Rainard
Ernault, Etienne
Gangaram‐Panday, Shanti
Passier, Paul
author_sort Treijtel, Nicoline
collection PubMed
description ASP8477 (molecular weight 325.36 g/mol) is a fatty acid amide hydrolase inhibitor intended for the treatment of neuropathic pain. Results from in vitro studies indicated that ASP8477 is a direct inhibitor of cytochrome P450 (CYP) 2C8, 2C9, 2C19, 2D6, and 3A4 enzymes at expected efficacious concentrations, with the strongest effect on CYP2C19; a phase 1 study confirmed ASP8477 to be a CYP2C19 inhibitor. To further evaluate the interaction potential of ASP8477, a cocktail interaction study was performed using the probe substrates of the validated Inje cocktail containing losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4). Because ASP8477 shows nonlinear pharmacokinetics, 3 doses (20, 60, and 100 mg) were evaluated. This study revealed changes in exposure (area under the concentration‐time curve) of the probe substrates after treatment with 20, 60, and 100 mg ASP8477, respectively, compared with substrates alone with geometric mean ratios of: midazolam, 119%, 151%, and 158%; losartan, 107%, 144%, and 190%; omeprazole, 213%, 456%, and 610%; and dextromethorphan, 138%, 340%, and 555% (with increasing doses, respectively). Overall, ASP8477 was a weak inhibitor for CYP3A4 and CYP2C9, a moderate to strong inhibitor for CYP2C19, and a weak to strong inhibitor for CYP2D6, with doses from 20 to 100 mg. This study confirmed that the Inje cocktail approach was able to detect relevant drug‐drug interactions impacting further development of ASP8477 and future therapeutic use. With the approach used here, the inhibiting effect of a perpetrator drug on different CYP enzymes can be evaluated, and at different doses, thereby supporting dose recommendations for potential interactions.
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spelling pubmed-65937272019-07-10 A Cocktail Interaction Study Evaluating the Drug‐Drug Interaction Potential of the Perpetrator Drug ASP8477 at Multiple Ascending Dose Levels Treijtel, Nicoline Collins, Christiane van Bruijnsvoort, Michel Fuhr, Rainard Ernault, Etienne Gangaram‐Panday, Shanti Passier, Paul Clin Pharmacol Drug Dev Articles ASP8477 (molecular weight 325.36 g/mol) is a fatty acid amide hydrolase inhibitor intended for the treatment of neuropathic pain. Results from in vitro studies indicated that ASP8477 is a direct inhibitor of cytochrome P450 (CYP) 2C8, 2C9, 2C19, 2D6, and 3A4 enzymes at expected efficacious concentrations, with the strongest effect on CYP2C19; a phase 1 study confirmed ASP8477 to be a CYP2C19 inhibitor. To further evaluate the interaction potential of ASP8477, a cocktail interaction study was performed using the probe substrates of the validated Inje cocktail containing losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A4). Because ASP8477 shows nonlinear pharmacokinetics, 3 doses (20, 60, and 100 mg) were evaluated. This study revealed changes in exposure (area under the concentration‐time curve) of the probe substrates after treatment with 20, 60, and 100 mg ASP8477, respectively, compared with substrates alone with geometric mean ratios of: midazolam, 119%, 151%, and 158%; losartan, 107%, 144%, and 190%; omeprazole, 213%, 456%, and 610%; and dextromethorphan, 138%, 340%, and 555% (with increasing doses, respectively). Overall, ASP8477 was a weak inhibitor for CYP3A4 and CYP2C9, a moderate to strong inhibitor for CYP2C19, and a weak to strong inhibitor for CYP2D6, with doses from 20 to 100 mg. This study confirmed that the Inje cocktail approach was able to detect relevant drug‐drug interactions impacting further development of ASP8477 and future therapeutic use. With the approach used here, the inhibiting effect of a perpetrator drug on different CYP enzymes can be evaluated, and at different doses, thereby supporting dose recommendations for potential interactions. John Wiley and Sons Inc. 2019-02-07 2019 /pmc/articles/PMC6593727/ /pubmed/30730615 http://dx.doi.org/10.1002/cpdd.660 Text en © 2019 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Articles
Treijtel, Nicoline
Collins, Christiane
van Bruijnsvoort, Michel
Fuhr, Rainard
Ernault, Etienne
Gangaram‐Panday, Shanti
Passier, Paul
A Cocktail Interaction Study Evaluating the Drug‐Drug Interaction Potential of the Perpetrator Drug ASP8477 at Multiple Ascending Dose Levels
title A Cocktail Interaction Study Evaluating the Drug‐Drug Interaction Potential of the Perpetrator Drug ASP8477 at Multiple Ascending Dose Levels
title_full A Cocktail Interaction Study Evaluating the Drug‐Drug Interaction Potential of the Perpetrator Drug ASP8477 at Multiple Ascending Dose Levels
title_fullStr A Cocktail Interaction Study Evaluating the Drug‐Drug Interaction Potential of the Perpetrator Drug ASP8477 at Multiple Ascending Dose Levels
title_full_unstemmed A Cocktail Interaction Study Evaluating the Drug‐Drug Interaction Potential of the Perpetrator Drug ASP8477 at Multiple Ascending Dose Levels
title_short A Cocktail Interaction Study Evaluating the Drug‐Drug Interaction Potential of the Perpetrator Drug ASP8477 at Multiple Ascending Dose Levels
title_sort cocktail interaction study evaluating the drug‐drug interaction potential of the perpetrator drug asp8477 at multiple ascending dose levels
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593727/
https://www.ncbi.nlm.nih.gov/pubmed/30730615
http://dx.doi.org/10.1002/cpdd.660
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