Population PKPD model
After the final PK model was established, the PKPD model was analyzed with a sequential approach using individual pharmacokinetic parameters with the standard error (IPPSE) method.36,37Steady-state oxypurinol concentration was linked to the PD model using a direct effect Emax model was tested, using the following equation:
\begin{equation} \text{Oxypurinol}_{\text{ss}}(mg/L)=\frac{150\ mg}{CL/f_{m}\ (L/h)\times 12\ (h)}\nonumber \\ \end{equation}\begin{equation} Post\ treatmnt\ SU\ (mg/dL)=\text{BL}_{\text{urate}}\ (mg/dL)-\ \frac{I_{\max}\ (mg/dL)\ \times\ \text{oxypurinol}_{\text{ss}}^{\gamma}\ (mg/L)}{\text{IC}_{50}^{\gamma}\ \left(mg/L\right)+\ \ \text{oxypurinol}_{\text{ss}}^{\gamma}\ (mg/L)}\nonumber \\ \end{equation}
where oxypurinolss is the serum oxypurinol concentration at steady-state; BLurate is the baseline SU;Imax is the maximum inhibitory effect of oxypurinol on xanthine dehydrogenase to inhibit urate production;IC50 is the oxypurinol concentration required to inhibit 50% of the activity of xanthine dehydrogenase; γ is the Hill coefficient for the sigmoid Emax model. The PKPD structural model is depicted in Figure 1 .