期刊
MOLECULES
卷 27, 期 20, 页码 -出版社
MDPI
DOI: 10.3390/molecules27206815
关键词
gilteritinib; OATP1B; itraconazole; pharmacokinetics; drug-drug interactions; CYP3A
资金
- National Institutes of Health [R01CA138744, U24CA247648, R01CA215802, F31CA254151]
- Cancer Center Support Grant by the OSU Comprehensive Cancer Center Pelotonia foundation [P30 CA02176]
- Pelotonia Fellowship Program
- Eli Lilly fellowship program
This study found that pretreatment with itraconazole significantly increased the systemic exposure to gilteritinib in mice, similar to the observed clinical drug-drug interaction. Furthermore, it revealed that gilteritinib is a substrate of OATP1B-type transporters and that the ability of itraconazole to inhibit OATP1B-type transport is dependent on its metabolism by CYP3A isoforms.
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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