Itraconazole-Induced Increases in Gilteritinib Exposure Are Mediated by CYP3A and OATP1B.
Molecules
; 27(20)2022 Oct 12.
Article
en En
| MEDLINE
| ID: mdl-36296409
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Leucemia Mieloide Aguda
/
Itraconazol
Límite:
Animals
Idioma:
En
Revista:
Molecules
Asunto de la revista:
BIOLOGIA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos