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.