Winnonlin 6

The plasma concentration–time profiles of cilostazol for each subject were analyzed by a noncompartmental method using WinNonlin^® 6.1 (Pharsight Corporation, Mountain View, CA, USA). All analyses were made using actual times of sampling. The area under the curve for a dosing interval (AUC_T) was calculated by the linear trapezoidal rule. The peak plasma concentration at steady state (C_max,ss) and the time to reach C_max,ss (t_max,ss) were determined from the observed values. The terminal elimination rate constant (λ_z) was estimated by linear regression of the terminal log-linear portion of the plasma concentration–time curves. The terminal elimination half-life (t_1/2β) was calculated for each subject as ln(2)/λ_z.
All statistical analyses were conducted using SAS^® 9.3 (SAS Institute, Cary, NC, USA) and WinNonlin 6.1 (Pharsight Corporation). Demographic data and PK results were summarized using descriptive statistics. For the comparison of PK characteristics between IR and SR formulations, the C_max,ss and AUC_T of each formulation were log-transformed and tested by a mixed-model analysis of variance. The mean differences and 90% confidence intervals (CIs) were back-transformed to obtain geometric mean ratios and CIs for those ratios. For the comparison of frequency of AEs between two formulations, P-value was obtained by a Fisher’s exact test.

Descriptive statistical analysis was performed for pharmacokinetic parameters. Quantitative indicators were summarized with descriptive statistics by arithmetic mean, standard deviation, median, minimum, maximum and geomean. Qualitative indicators were used for descriptive statistics using frequency or number and percentage of subjects. After transformation of C_max, AUC_0-t and AUC_0-∞ to their logarithmic (Ln) values, analysis of variance (ANOVA) was conducted using a linear-mixed model to evaluate the effects of period, treatment, sequence, and subjects with WinNonlin^® 6.4 (Pharsight Corporation, Mountain View, CA, USA). Additionally, the bioequivalence between the two formulations was assessed by two one-sided t-tests and the 90% confidence intervals (CIs) analysis. The Wilcoxon signed-rank test was performed on the nonparametric nature of T_max. The acceptance criteria for bioequivalence were that the 90% CIs of the geometric mean ratios of the test formulation to the reference formulation were completely within 80.0–125.0% for the AUC and C_max.

The pharmacokinetics of paclitaxel was assessed by plotting the area under the plasma concentration-time curve (AUC) for 24 hours, commencing immediately before administration (AUC_0-24). Blood samples were obtained prior to infusion and immediately before and one, three, five, and 23 hours after the end of the infusion. The plasma drug concentration was measured by high-performance liquid chromatography with tandem mass spectrometry (18 (link)). Pharmacokinetic parameters were calculated according to the two-compartment model using the nonlinear least squares method in WinNonlin 6.4 (Pharsight, Inc., Mountain View, CA). Furthermore, we calculated the dose intensity (mg/m²/wk) of paclitaxel as the cumulative dose (mg/m²) divided by the administration period.