Winnonlin version 6

Standard non-compartmental methods using WinNonlin version 6.4 (Certara United States of America Inc,.) were used to analyze plasma PK data, including peak plasma concentration (C_max), time to peak plasma concentration (T_max), area under the plasma concentration–time curve from time 0 to the last timepoint with a quantifiable concentration (AUC_0-t), AUC from time 0 to infinity (AUC_0-∞), t_1/2, clearance (CL/F), and apparent volume of distribution (Vz/F).
Statistical analysis was performed using SAS software, version 9.4 (SAS Institute Inc., United States). Continuous variables were reported as number, mean with standard deviation, median, maximum, and minimum. Categorical variables, were reported as frequency and percentage. Dose proportionality was explored using a regression power model, relating log-transformed C_max and AUC and log-transformed dose.

PK parameters were estimated with noncompartmental methods using WinNonlin version 6.4 (Certara, Princeton, NJ). The peak plasma concentration (C_max) and time to reach the peak plasma concentration (T_max) were calculated from the actual plasma concentration data. The area under the plasma concentration-time curve from zero to the last measurable concentration (AUC_0-t) was calculated via the linear trapezoidal rule. The AUC_0-∞ was calculated using the following formula: AUC_0-∞ = AUC_0-t + C_t/k_e, where C_t is the last plasma concentration measured. The terminal elimination half-life (t_1/2) was calculated as 0.693/k_e. The oral clearance (CL/F) and volume of distribution (V_z/F) were defined as Dose/AUC_0-∞ and Dose/(k_e·AUC_0-∞), respectively.