Abstract:
Brivanib alaninate is the orally available prodrug of
brivanib, a dual inhibitor of fibroblast growth factor and
vascular endothelial growth factor signaling pathways
that is under therapeutic investigation for various malignancies.
Brivanib alaninate inhibits CYP3A4 in vitro, and
thus there is potential for drug-drug interaction with
CYP3A4 substrates, such as midazolam. The present
study evaluated pharmacokinetic parameters and safety/
tolerability upon coadministration of brivanib alaninate
and midazolam. Healthy participants received intravenous
(IV) or oral midazolam with and without oral brivanib
alaninate. Blood samples for pharmacokinetic analysis
were collected up to 12 hours after midazolam and up to
48 hours after brivanib alaninate. Twenty-four participants
were administered study drugs; 21 completed the trial. No clinically relevant effect of brivanib alaninate on
the overall exposure to midazolam following IV or oral
administration was observed. Orally administered brivanib
alaninate was generally well tolerated in the presence of
IV or oral midazolam. The lack of a pharmacokinetic
interaction between brivanib and midazolam indicates
that brivanib alaninate does not influence either intestinal
or hepatic CYP3A4 and confirms that brivanib alaninate
may be safely coadministered with midazolam and other
CYP3A4 substrates.
