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-∞.