Limitations
A number of limitations should be noted. First, the small sample size (n=34) limits the ability to identify important covariates that could further explain the BSV in PKPD parameters of oxypurinol. However, the significant association between SLC22A12 rs505802 genotype and oxypurinol clearance, and PDZK1 rs1219861 genotype withIC50 in this population but not in other populations highlight the importance of including diverse populations in clinical studies. In other words, these observations may be unique to the Hmong population studied. Secondly, PK sampling scheme only covered half of the dosing interval that may negatively impact the accuracy of oxypurinol PK parameters estimate. This was a design feature suggested by the Hmong Genomics Board based on respecting the practical limitations of our participants. Given oxypurinol likely exhibits one compartmental PK behavior that is in concordance with previous studies26,27,29,31 and the maximum oxypurinol concentration observed in our study was at 2 hours, these provide confidence in our estimates. In addition, although we identifiedSLC22A12 rs505802 and PDZK1 rs1219861 are key determinants for PKPD response of oxypurinol, these SNPs are in the non-coding region, thus the causal SNPs for the differences observed inCL/fm and IC50 among individuals with different genotypes require further investigation. As this was a pilot study in this unique population, the proposed allopurinol maintenance dose to achieved target SU requires validation in a prospective clinical study in a larger Hmong population.