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 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.

A Drug–Drug Interaction Study to Evaluate the Impact of Simvastatin and Itraconazole on Erlotinib Pharmacokinetics in Rats by UPLC-MS/MS

“…of erlotinib. These results were generally consistent with the published literature, [30][31][32] which indicated there were no meaningful pharmacokinetic DDIs between gilteritinib and itraconazole once daily for seven days. However, a single dose of itraconazole increased the gilteritinib systemic exposure in rats.…”

Comparing the Real-World Use of Isavuconazole to Other Anti-Fungal Therapy for Invasive Fungal Infections in Patients with and without Underlying Disparities: A Multi-Center Retrospective Study

“…Another concern related to triazole use are the drug-drug interactions with the targeted chemotherapies for hematological malignancies such as Ruxolitinib, Venetoclax and Gilteritinib, etc. ; [ 33 , 34 , 35 ]. However, most new drugs undergo extensive hepatic metabolism and exhibit moderate to severe drug-drug interactions with triazole antifungal agents, commonly increasing the levels of targeted therapies in hematologic malignancy with severe side effects such as severe and prolonged neutropenia [ 36 , 37 ].…”