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Drug Interactions of Vebreltinib, a Novel Type I c-Met Inhibitor, Coadministration With Rifampin or Itraconazole in
Jingcheng Chen1,2, Jingxuan Wu1,2, Yuqin Song1,2
1Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Abstract:
Vebreltinib is a novel, highly selective type I c-Met inhibitor developed for treating non-small cell lung cancer (NSCLC) and glioma. As in vitro studies indicate that vebreltinib is primarily metabolized via cytochrome P450 (CYP) 3A4, this study aimed to characterize the drug-drug interaction (DDI) potential of vebreltinib with strong CYP3A4 modulators. Following a preliminary single ascending dose (SAD) study to establish baseline safety and pharmacokinetics (PK) in healthy participants, a DDI study was designed to evaluate the impact of the strong CYP3A4 inducer rifampin and the strong CYP3A4 inhibitor itraconazole on vebreltinib exposure. In the CYP3A4 induction part of the DDI study, participants (n = 14) received 200 mg vebreltinib on Days 1 and 15, with rifampin (600 mg once daily) administered on Days 8-21. In the inhibition part, participants (n = 14) received 200 mg vebreltinib on Days 1 and 11. Itraconazole was administered as a loading dose (200 mg BID on Day 8) followed by maintenance dosing (200 mg QD from Days 9 to 19). PK blood samples were collected at predetermined time points. Vebreltinib plasma concentrations were assessed using a validated liquid chromatography-tandem mass spectrometry (LC-MS) method. Co-administration with rifampin reduced the AUC0-t and AUC0-∞of vebreltinib by ~65% and ~66%, respectively, whereas the Cmax did not change significantly. In contrast, coadministration with itraconazole led to an increase in the AUC and Cmax of vebreltinib by about 56% and 46%, respectively. Vebreltinib, both alone and in combination with rifampin or itraconazole, was well tolerated in healthy participants.
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