INTRODUCTION
Allopurinol is the first-line urate-lowering therapy (ULT) to prevent
gout by lowering serum urate (SU) to a target of 6 mg/dL in all patients
who can tolerate the medication.1 The treat-to-target
SU level approach instead of a fixed dose ULT strategy has been
recommended by American College of Rheumatology and other
organizations.2-4 Nonetheless, only 20-50% of
patients achieve target SU within the US and Europe.5Patients who typically fail to achieve SU targets include those who have
high SU (>9 mg/dL), moderate-to-severe chronic kidney
disease (CKD stage ≥3), or urolithiasis. Patients with aforementioned
conditions have a greater risk for gout flares and tophi
formation.6,7 Additionally, hyperuricemia (defined as
SU ≥6.8 mg/dL) is strongly associated with other chronic conditions,
including hypertension,8,9 type 2 diabetes mellitus
(T2DM),10 metabolic syndrome,11cardiovascular diseases (CVD) 12 and dyslipidemia with
elevated low-density lipoprotein (LDL) cholesterol and
hypertriglyceridemia.13
To optimize allopurinol use, several strategies have been proposed. One
approach projects an allopurinol maintenance dose based on creatinine
clearance (CrCl).14 However, this approach was
developed with the specific goal to avoid the allopurinol-induced severe
cutaneous adverse reaction (SCAR) and not to achieve target SU. This
approach may be sensible because impaired renal function correlated with
the development and poor prognosis of allopurinol induced
SCAR.15-17 Given this CrCL-based dose approach, it is
understandable that only 19% of patients achieved target
SU.18 Starting allopurinol dose based on estimated
glomerular filtrate rate (eGFR) has been proposed.19Similarly, the goal was to prevent allopurinol-induced SCAR, with the
authors asserting that the starting dose, not the maintenance dose,
correlated with the incidence of allopurinol-induced SCAR. Stamp et al19 reported that dose titration is often required to
achieve target SU in patients who tolerate allopurinol. An approach that
encourages safe targeting of optimal allopurinol dosage to achieve
target SU remains elusive. This situation creates a gap in tools that
specifically address the goal of dose optimization with the intended
purpose of mitigating acute and chronic complications associated with
hyperuricemia and gout.
Genome-wide association studies (GWAS) provide insights on how single
nucleotide polymorphisms (SNPs) in key transporter genes can impact
treatment outcomes. The ABCG2 (BCRP) rs2231142C>A is
associated with SU-lowering response to allopurinol20-23 and has been suggested as a guide to improve
drug dosage and/or selection by identifying patients in need of
alternate therapeutic approaches. The SLC22A12 (URAT1)
rs505802C>T is not only associated with the risk of
hyperuricemia,24 but also importantly associated with
the exposure of serum oxypurinol, the active metabolite of
allopurinol.25 These two transporters, BRCP and URAT1,
may prove to be important when identifying genomic based sources of
variability in response to allopurinol.
Several population pharmacokinetics (PK)26,27 and
pharmacokinetic-pharmacodynamic (PKPD)28-31 models
have been developed. Despite these models identifying that body mass,
renal function, and concomitant medications, including diuretics and
uricosurics, are important factors, none of the studies illustrated a
strong association between SNPs and either PK or PD parameters for
oxypurinol. Furthermore, most of the studied populations are of European
descent.
The aims of this project were to (1) develop a population PKPD model to
characterize the relationship between serum oxypurinol and SU, (2)
quantify the effects of relevant clinical characteristics and SNPs
identified from GWAS on the PKPD effects for oxypurinol, and (3) predict
the allopurinol maintenance dose to achieve target SU of <6
mg/dL.