Abstract
Background Famitinib is an oral, small-molecule, multi-targeted tyrosine
kinase inhibitor under clinical investigation for the treatment of solid
tumors. As famitinib is metabolized mainly by cytochrome P450 3A4
(CYP3A4), the study was conducted to investigate the effect of potent
CYP3A4 inducer rifampin on the pharmacokinetics of famitinb. Methods
This single-center, single-arm and fixed-sequence drug-drug interaction
study enrolled 21 healthy Chinese male subjects. Subjects received a
single oral dose of famitinib 25 mg on days 1 and 16 and repeated
administration of oral rifampin 600mg once daily on days 10-23. Blood
samples were collected and plasma concentrations of famitinib were
measured by validated liquid chromatography-tandem mass spectrometry
(LC-MS/MS) method. Pharmacokinetic parameters were calculated using
noncompartmental analysis and safety was assessed. Results In the
presence of rifampin, the famitinib geometric mean maximum plasma
concentration (Cmax) and area under the plasma concentration-time curve
from time zero to infinity (AUC0-∞) decreased by 48% and 69%,
respectively, and the mean elimination half-life was shortened from 33.9
h to 18.2 h. The GMR of famitinib Cmax and AUC0-∞ and their 90% CI were
0.52 (0.50, 0.54) and 0.31 (0.29, 0.33). Single dose of famitinib 25mg
was well tolerated and 8 subjects (38.1%) reported treatment emergent
adverse events. Conclusion Co-administration of rifampin considerably
reduces plasma concentration of famitinb due to CYP3A4 induction.
Concomitant administration of famitinib and strong CYP3A4 inducers
should be avoided, whereas when simultaneous use with inducers of
CYP3A4, dose adjustment of famitinb is recommended.