Simulations to predict allopurinol maintenance dose
Simulation was performed to examine the impact of important covariates on the serum oxypurinol and urate concentration. Different dosing strategies under a combination of significant covariates in the final PKPD model to achieve target SU of < 6mg/dL were performed for 1000 simulations for a total of 91,584 virtual patients. The distribution of PKPD model parameters were based on the final PKPD model. The model identified maintenance dose was the lowest dose that could achieve the target SU <6mg/dL in at least 75% of the cases. Simulation considerations were based on previous publication29 with a few exceptions. First, the maintenance dose of allopurinol was considered from 50 to 800 mg/day because a maximum of 800 mg/day was approved by the US FDA. Second, creatinine clearance was simulated between 15 to 120 mL/min in 1 mL/min increment then stratified into 15-30 mL/min, 30-60 mL/min, and ≥ 60 mL/min categories. Third, FFM between 50 to 100 kg with 10 kg increment was considered. The impact of SLC22A12 rs505802 CC, CT, TT genotypes on oxypurinol CL/fm and the impact ofPDZK1 rs12129861 GG, GA, and AA genotypes onIC50 were considered (see Result section for the rationale for the selection of these covariates). Simulations were performed using R software (version 4.1.0)45.