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Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B

Gilteritinib, an FDA-approved tyrosine kinase inhibitor approved for the treatment of relapsed/refractory FLT3-mutated acute myeloid leukemia, is primarily eliminated via CYP3A4-mediated metabolism, a pathway that is sensitive to the co-administration of known CYP3A4 inhibitors, such as itraconazole...

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Autores principales: Garrison, Dominique A., Jin, Yan, Talebi, Zahra, Hu, Shuiying, Sparreboom, Alex, Baker, Sharyn D., Eisenmann, Eric D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9610999/
https://www.ncbi.nlm.nih.gov/pubmed/36296409
http://dx.doi.org/10.3390/molecules27206815
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author Garrison, Dominique A.
Jin, Yan
Talebi, Zahra
Hu, Shuiying
Sparreboom, Alex
Baker, Sharyn D.
Eisenmann, Eric D.
author_facet Garrison, Dominique A.
Jin, Yan
Talebi, Zahra
Hu, Shuiying
Sparreboom, Alex
Baker, Sharyn D.
Eisenmann, Eric D.
author_sort Garrison, Dominique A.
collection PubMed
description Gilteritinib, an FDA-approved tyrosine kinase inhibitor approved for the treatment of relapsed/refractory FLT3-mutated acute myeloid leukemia, is primarily eliminated via CYP3A4-mediated metabolism, a pathway that is sensitive to the co-administration of known CYP3A4 inhibitors, such as itraconazole. However, the precise mechanism by which itraconazole and other CYP3A-modulating drugs affect the absorption and disposition of gilteritinib remains unclear. In the present investigation, we demonstrate that pretreatment with itraconazole is associated with a significant increase in the systemic exposure to gilteritinib in mice, recapitulating the observed clinical drug–drug interaction. However, the plasma levels of gilteritinib were only modestly increased in CYP3A-deficient mice and not further influenced by itraconazole. Ensuing in vitro and in vivo studies revealed that gilteritinib is a transported substrate of OATP1B-type transporters, that gilteritinib exposure is increased in mice with OATP1B2 deficiency, and that the ability of itraconazole to inhibit OATP1B-type transport in vivo is contingent on its metabolism by CYP3A isoforms. These findings provide new insight into the pharmacokinetic properties of gilteritinib and into the molecular mechanisms underlying drug–drug interactions with itraconazole.
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spelling pubmed-96109992022-10-28 Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B Garrison, Dominique A. Jin, Yan Talebi, Zahra Hu, Shuiying Sparreboom, Alex Baker, Sharyn D. Eisenmann, Eric D. Molecules Article Gilteritinib, an FDA-approved tyrosine kinase inhibitor approved for the treatment of relapsed/refractory FLT3-mutated acute myeloid leukemia, is primarily eliminated via CYP3A4-mediated metabolism, a pathway that is sensitive to the co-administration of known CYP3A4 inhibitors, such as itraconazole. However, the precise mechanism by which itraconazole and other CYP3A-modulating drugs affect the absorption and disposition of gilteritinib remains unclear. In the present investigation, we demonstrate that pretreatment with itraconazole is associated with a significant increase in the systemic exposure to gilteritinib in mice, recapitulating the observed clinical drug–drug interaction. However, the plasma levels of gilteritinib were only modestly increased in CYP3A-deficient mice and not further influenced by itraconazole. Ensuing in vitro and in vivo studies revealed that gilteritinib is a transported substrate of OATP1B-type transporters, that gilteritinib exposure is increased in mice with OATP1B2 deficiency, and that the ability of itraconazole to inhibit OATP1B-type transport in vivo is contingent on its metabolism by CYP3A isoforms. These findings provide new insight into the pharmacokinetic properties of gilteritinib and into the molecular mechanisms underlying drug–drug interactions with itraconazole. MDPI 2022-10-12 /pmc/articles/PMC9610999/ /pubmed/36296409 http://dx.doi.org/10.3390/molecules27206815 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Garrison, Dominique A.
Jin, Yan
Talebi, Zahra
Hu, Shuiying
Sparreboom, Alex
Baker, Sharyn D.
Eisenmann, Eric D.
Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B
title Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B
title_full Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B
title_fullStr Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B
title_full_unstemmed Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B
title_short Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B
title_sort itraconazole-induced increases in gilteritinib exposure are mediated by cyp3a and oatp1b
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9610999/
https://www.ncbi.nlm.nih.gov/pubmed/36296409
http://dx.doi.org/10.3390/molecules27206815
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