2.6 Safety assessment
All subjects were assessed for tolerability and safety parameters during
the entire study. Safety was monitored by measurements of vital signs
(blood pressure, heart rate and temperature), physical examination
clinical laboratory tests and 12-lead electrocardiogram. Tolerability
was assessed by recording adverse events (AEs). Details of any AEs were
recorded, including the AEs types, incidence, severity (graded according
to NCI-CTCAE5.0), onset and end time, serious AEs, correlation with the
test drug, and outcomes.
2.7Pharmacokinetic and
Statistical Analysis
The concentration of the famitinib and the metabolite SHR116637 was
determined by LC-MS/MS. The PK parameters of above analytes were
calculated using a standard noncompartmental analysis method (NCA) by
Phoenix WinNonlin (Pharsight Corporation 8.3 or higher). The main
evaluation indices were C max (maximum plasma
concentration), the area under the curve of plasma concentration-time
from zero to the last measurable concentration calculated by the linear
trapezoid method (AUC 0 −t), and the area under
the curve of blood concentration from zero to infinity
(AUC 0−∞). The secondary evaluation indices wereT max, elimination half life
(t1/2), apparent clearance rate (CL/F), and apparent
volume of distribution (Vz/F). In addition, CL/F and Vz/F were not
applicable to the metabolite SHR116637.
Statistical analysis was carried out using SAS v 9.4 (SAS Institute,
Cary, NC, USA). Descriptive statistics and lists of PK parameters of the
analyte were conducted and mean concentration–time curves were plotted.
After natural log transformation, a mixed-effect model was used to fit
PK parameters. Based on this model, the drugs were considered as fixed
effects and the volunteers as random effects. The GMRs
(co-administration of famitinib and omeprazole, and administration of
famitinib alone) and their 90% CIs were estimated.