Pharmacokinetic and Statistical Analyses
According to only one literature, the intra-subject coefficient of variation (ISCV) for maximum plasma concentration (Cmax) was 17.0%. Since there was insufficient information for ISCV, sample size was chosen as 30 subjects in order to demonstrate bioequivalence for a 2x2 crossover design.
Cmax and area under the curve from time 0 to the last measurable concentration (AUC0-tlast) were considered as the primary target variables; area under the curve from time 0 to the infinite time (AUC0-∞), time to reach the peak concentration (tmax), terminal half life (t½), terminal disposition rate constant (λz) and mean residence time (MRT) were declared as the secondary target variables in this bioequivalence study.
Cmax and tmax for Favipiravir were obtained directly by plasma concentration-time curves. AUC0-tlast was calculated using the trapezoidal rule. AUC0-∞was calculated by summing AUC0-tlast and extrapolated area. The latter was determined by dividing the last measuredconcentration by λz which was estimated byregression of the terminal log-linear plasma concentration time points.
Cmax and AUC0-tlast were tested for statistically significant differences by means of the Analysis of Variance (ANOVA) test procedure after logarithmic transformation (ln). The effects of ANOVA were treatment, period, sequence and subject within the sequence and tested at 5% level of significance.
In the assessment of bioequivalence, confidence intervals approach was used. The two one-sided hypothesis at the 5% level of significance were tested by constructing the 90% confidence intervals (90% CIs) for the geometric mean ratios of test/reference products. The two formulations were considered as bioequivalent if the 90% CIs were within 80.00-125.00% for Cmax and AUC0-tlast. Difference in tmax was evaluated non-parametrically.
All statistical analysis were done using Phoenix WinNonlin (Version 8.1, Certara L.P.).
Also, ANOVA and determination of 90% CIs were applied to non-logaritmic transformed data of tmax, t1/2, λz and MRT and to ln transformed data of AUC0-∞.