“Alternative” indicates an alternative medicine is preferred over allopurinol, given that the target serum urate was not achieved despite the maximum dose of allopurinol (800 mg/day). CrCL, creatinine clearance.

Figure 1. The structural model of the pharmacokinetics and pharmacodynamics effect of allopurinol

BL_urate , baseline serum urate; C, serum oxypurinol concentration; CL, apparent oxypurinol clearance;f_m , fraction of the allopurinol dose systemically converts to oxypurinol; K_fm , combined absorption and formation rate constant; I_max , maximum inhibitory effect of oxypurinol on xanthine dehydrogenase to inhibit urate production; IC₅₀ , oxypurinol concentration required to inhibit 50% of the activity of xanthine dehydrogenase; IPPSE, individual pharmacokinetic parameters with standard error; V, apparent oxypurinol volume of distribution

Figure 2. Goodness-of-fit plots of the final PKPD models for oxypurinol.

A and B, observed versus population-predicted concentration for serum oxypurinol and serum urate. C and D, observed versus individual-predicted concentration for serum oxypurinol and serum urate. E and F, conditional weighted residuals versus population-predicted concentration for serum oxypurinol and serum urate. CWRES = conditional weighted residuals.

Figure 3. Visual predictive checks of the final PKPD models for oxypurinol. A, serum oxypurinol concentration stratified by SLC22A12 rs505802 genotypes. B, serum urate concentration stratified by SLC22A12 rs505802 genotypes. The open circles represent the observed data, and the blue and red lines represent the 5, 50, and 95th percentiles of the observed data. The blue and shaded areas are the 95% confidence intervals of the simulated concentrations for the corresponding percentile values.