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

ABSTRACT: 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 furt

SUBMITTER: Garrison DA 

PROVIDER: S-EPMC9610999 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature