## 4 Discussion
Setting the absorption rate constant to be \"0.5x\" and \"2x\" of what was originally estimated from the NLME analysis was considered a rational choice for slower and faster absorption, respectively. Slower or faster absorption kinetics, compared to those above, would not offer any advantage or alter the results. Moreover, the use of simulated conditions for the actual data (i.e., the \"1x-\" scenario) allowed to verify the findings obtained from the original dataset. From the analysis made in this study, it was shown that the metric best reflecting the rate of absorption, among those examined, is the Cmax/Tmax ratio. The latter was found to better reflect the absorption rate, regardless of the absolute kinetic properties of absorption. It should be underlined that Cmax/Tmax is not proposed to be the best measure for absorption rate, but the two machine learning algorithms uncovered its better suitability compared to the other PK metrics explored (e.g., Cmax, Cmax/AUC). \begin{table}
\begin{tabular}{c c c} \hline
**Purpose** & **Action** & **Main Findings** \\ \hline \hline \multirow{7}{*}{B4. Contribution of PK variables to Cmax, Cmax/Tmax} & \multirow{7}{*}{Random forest to Cmax, Cmax/AUC, Cmax/Tmax for each of the 3 simulated datasets (0.5\%., 1x-, 2x-)} & - Verified the findings identified in A2 \\  & & - As absorption kinetics becomes faster, the contribution of Tmax into Cmax or \\  & & \multicolumn{1}{c}{Cmax/AUC becomes less} \\  & & \multicolumn{1}{c}{Cmax/AUC, Cmax/AUC, Cmax/Tmax for each of the 3 simulated datasets (0.5\%., 1x-, 2x-)} & - As absorption kinetics becomes faster, the contribution of Tmax into Cmax/Tmax \\ \cline{1-1}  & & \multicolumn{1}{c}{} & - Cmax/Tmax reflects better the kinetic properties of absorption rate, regardless the kinetic properties of absorption \\ \hline \hline \end{tabular}
\end{table} 
Table 3: _Cont._A possible argument against the use of Cmax/Tmax could arise from the fact that the latter relies on Tmax, which is known to have some limitations due to the fact that it is measured on a discrete scale and can be highly variable due to insufficient sampling. For this reason, it was actually stated in the EMA 2001 guideline that Tmax should be analyzed as a discrete attribute using the non-parametric 90% confidence interval [26]. The existing EMA guideline states that a statistical analysis of Tmax, which is only necessary when a rapid release is clinically relevant for the initiation of action or linked to adverse events, should compare the median values and its variability between test and reference products [1]. However, the possible problems due to sampling are counterbalanced with a frequent sampling schedule at early time points, before Tmax, which is actually required by the guidelines [1,2]. In this study, the simulated BE datasets were generated assuming a sampling interval of 15 min in order to avoid adding bias to the estimations of the PK parameters. The frequency of this sampling scheme was adequate not only for the typical case (\"1x-\") and the slow absorption (\"0.5x-\"), but also for the fast absorption scenario (\"2x-\"). It should be reminded that typically the Tmax of donepezil is anticipated to appear between 3-4 h post dose [27]. The fact that Tmax is a discrete variable, since it is dependent on sampling, has already been addressed in the literature [11,28]. It has been reported that Tmax defines a count process that encompasses the rate of absorption if it is acquired at equally spaced sample periods during the suspected absorption phase. Furthermore, such count data appear to follow the single parameter Poisson distribution, which characterizes the rate of many discrete processes and so provides the appropriate theoretical foundation for comparing two or more formulations for differences in absorption rate. Besides, the sampling schedule at early time points is already frequent, so Tmax can be easily converted into a count variable. These observations have revealed the usefulness of Tmax as an absorption rate measure [11,28].