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.