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.