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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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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. |
format | Online Article Text |
id | pubmed-9610999 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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