期刊
PHARMACEUTICS
卷 14, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics14040694
关键词
venetoclax; antifungal; pharmacokinetics; CYP3A
资金
- National Institutes of Health [R01CA138744, U24CA247648, R01CA215802, F31CA254151]
- OSU Comprehensive Cancer Center Pelotonia Foundation
- Pelotonia Fellowship Program
- Biff Ruttenberg Foundation
- Adventure Alle Fund
- Beverly and George Rawlings Directorship
- EP Evans Foundation
- NIH
The study found that antifungal drugs can increase Venetoclax exposure by inhibiting both CYP3A-mediated metabolism and OATP1B-mediated transport, especially antifungal drugs such as ketoconazole and micafungin. These findings have important implications for the co-administration of drugs that inhibit both CYP3A-mediated metabolism and OATP1B-mediated transport.
Venetoclax, a BCL-2 inhibitor used to treat certain hematological cancers, exhibits low oral bioavailability and high interpatient pharmacokinetic variability. Venetoclax is commonly administered with prophylactic antifungal drugs that may result in drug interactions, of which the underlying mechanisms remain poorly understood. We hypothesized that antifungal drugs may increase venetoclax exposure through inhibition of both CYP3A-mediated metabolism and OATP1B-mediated transport. Pharmacokinetic studies were performed in wild-type mice and mice genetically engineered to lack all CYP3A isoforms, or OATP1B2 that received venetoclax alone or in combination with ketoconazole or micafungin. In mice lacking all CYP3A isoforms, venetoclax AUC was increased by 1.8-fold, and pretreatment with the antifungal ketoconazole further increased venetoclax exposure by 1.6-fold, despite the absence of CYP3A. Ensuing experiments demonstrated that the deficiency of OATP1B-type transporters is also associated with increases in venetoclax exposure, and that many antifungal drugs, including micafungin, posaconazole, and isavuconazole, are inhibitors of this transport mechanism both in vitro and in vivo. These studies have identified OATP1B-mediated transport as a previously unrecognized contributor to the elimination of venetoclax that is sensitive to inhibition by various clinically-relevant antifungal drugs. Additional consideration is warranted when venetoclax is administered together with agents that inhibit both CYP3A-mediated metabolism and OATP1B-mediated transport.
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