## 2 Materials and Methods
### Estimation of the Pharmacokine Parameters  
Table 1 summarizes the pharmacokinetic parameters utilized in this study. All these parameters were calculated using model-independent methods (PKanalixTM, MonolixSuiteTM, v2021R2). Among them, there are traditional metrics like AUCt, Cmax, Tmax, the terminal slope (lambda), as well as average concentration (Cavg), the proportion Cmax/Cavg, and the Cmax/AUC ratio, which has been proposed as an indirect measure of the absorption rate. In addition, the partial AUC from time zero up to the median Tmax of the reference product (AUCp) was determined because it has been proposed as a marker of early drug exposure [3]. \begin{table}
\begin{tabular}{l l l} \hline \hline
**Parameter** & **Description** & **Software** \\ \hline Cmax & Maximum observed plasma concentration & \begin{tabular}{l} PKanalixTM \\ (Monolix SuiteTM 2021R2) \\ \end{tabular} \\ \hline AUCt & Area under the concentration-time curve from time zero to the time of the last measurable concentration & \begin{tabular}{l} PKanalixTM \\ (Monolix SuiteTM 2021R2) \\ \end{tabular} \\ \hline AUCinf & Area under the Concentration-time curve extrapolated to infinity & \begin{tabular}{l} PKanalixTM \\ (Monolix SuiteTM 2021R2) \\ \end{tabular} \\ \hline AUCp & \begin{tabular}{l} Partial AUC from time zero up to the median Tmax of the \\ reference product \\ \end{tabular} & \begin{tabular}{l} PKanalixTM \\ (Monolix SuiteTM 2021R2) \\ \end{tabular} \\ \hline Tmax & Time at which Cmax is observed & \begin{tabular}{l} PKanalixTM \\ (Monolix SuiteTM 2021R2) \\ \end{tabular} \\ \hline Cavg & \
\begin{tabular}{l} Average concentration calculated as the ratio of AUCt over the time of last measurement \\ \end{tabular} &
\begin{tabular}{l} PKanalixTM \\ (Monolix SuiteTM 2021R2) \\ \end{tabular} \\ \hline Cmax/AUC & Ratio of Cmax to AUCt & Excel® Microsoft Office 365 \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Pharmacokine parameters utilized in the study. Apart from the PK parameters outlined above, which have already been proposed in the literature, two more metrics of absorption rate were investigated in this study. The first one is the Cmax/Tmax ratio, which was introduced and explored in a recent study [23]. The latter was found to better reflect the absorption rate compared to all other already-proposed metrics. So, in this study, its properties were further investigated to unveil their properties under more pharmacokinetic conditions (e.g., sampling schemes and absorption rate characteristics). The Cmax/Tmax ratio actually refers to the tangent of the slope defined by Cmax and Tmax (Figure 1a). A potential limitation of Cmax/Tmax could be the fact that it relies on a single measurement of time (i.e., Tmax) and the corresponding measured concentration (i.e., Cmax). Thus, an alternative estimation method of \"slope\" is introduced in this study, which utilizes all available C-t data up to Cmax. The new metric, termed \"average slope\", is the average of all slopes formed between two consecutive time points (Figure 1b). The slope (i.e., the tangent) between two sequential time points (times t\({}_{i+1}\) and t\({}_{i}\)) can be estimated by the ratio of change in the y-coordinates (i.e., concentration) over the change in the x-coordinates (i.e., time), Equation (1):  
\[\text{slope}_{i}=\frac{C_{i+1}-C_{i}}{t_{i+1}-t_{i}} \tag{1}\]  
Thus, the AS (i.e., average slope), which is the mean of these slopes, can be calculated as:  
\[\text{AS}=\frac{\sum_{i=1}^{n-1}\text{slope}_{i}}{n-1}=\frac{\sum_{i=1}^{n-1} \frac{C_{i+1}-C_{i}}{t_{i+1}-t_{i}}}{n-1} \tag{2}\]  
where n refers to the number of sampling points up to Tmax. Since there are n points between time zero and Tmax, there are n - 1 intervals that can be used to estimate slope