DISCUSSION
Allopurinol is the first-line ULT; however, many patients fail to
achieve target SU on allopurinol. We developed a population PKPD model
and identified the importance of clinical variables on the PKPD
parameters in Hmong participants with gout and/or hyperuricemia. Body
mass (FFM), renal function (estimated CrCL), and SLC22A12rs505802C>T are key determinants to the PK of oxypurinol.
Baseline SU, estimated CrCL, and PDZK1 rs12129861G>A
are important covariates to the PD of oxypurinol. When determining the
minimum allopurinol maintenance dose to achieve target SU, all of the
aforementioned clinical factors need to be considered.
The final estimated population oxypurinol clearance
[CL/fm of 1.05 L/h (95%CI 0.88-1.31)] was
similar to a previous study (1.32 L/h)29 where the
study participants had similarly estimated CrCL (70 mL/min versus 87
mL/min in GOUT-H). The final estimated population oxypurinol volume of
distribution [V/fm of 59.3 L (95%CI
51.3-71.9)] was higher than the aforementioned study (41.6 L),
possibly due to the older mean age of participants in their study
(60-year-old versus 43-year-old in GOUT-H) and their approach to adjust
for body mass (TBW versus FFM in GOUT-H). Given that the plasma protein
binding for oxypurinol is negligible, the distribution of oxypurinol is
similar to water content.49 Since elderly typically
have 10-15% less total body water compared to younger
individuals,50 the higher observed volume of
oxypurinol (V/fm ) in our population is expected.
The final estimated population parameters for the PD model
(BLurate : 9 mg/dL, Imax :
7.6 mg/dL, IC50 : 17.6 mg/L) were similar to
participants with gout and/or hyperuricemia
(BLurate : 8.5 mg/dL or 0.511 mmol/L,Imax : 6.87 mg/dL or 0.409 mmol/L,IC50 : 14.1 mg/L or 83.9
µmol/L)29 but different from the healthy participants
(BLurate : 4.6 mg/dL, Imax :
1 mg/dL, IC50 : 2.59 mg/L).31Higher Imax value observed in patients with
hyperuricemia suggests the maximum SU lowering effect of allopurinol
depends on the baseline SU level. The considerably higherIC50 in patients with gout and/or hyperuricemia
indicates that the potency of allopurinol is much lower and thus
requires a higher dose of allopurinol to achieve the same effect
compared to non-hyperuricemic adults.
Similar to previous findings27,29, we found that FFM
predicts oxypurinol clearance and volume of distribution better than
TBW. Since the majority of our study participants were either overweight
or obese, FFM approximates the lean body weight
better39 and better reflects the true volume of
distribution of oxypurinol. Renal function also plays a critical role in
both PK and PD of oxypurinol, which has been demonstrated in previous
population PKPD analyses and clinical studies.51-53Contrary to a clinical observation that a lower allopurinol dose is
needed to achieve target SU in patients with renal impairment (CrCl≤60
ml/min) compared with patients with CrCl >60
ml/min,51 we predicted that a higher allopurinol dose
is required in patients with renal impairment. Although estimated CrCL
is positively associated with both CL/fm andBLurate in the PKPD model, the overall
contribution of renal function is larger inBLurate . This observation was consistent with
previous published PKPD model29 where a higher
allopurinol dose was required in patients with renal impairment compared
to those without renal impairment if patients were taking diuretics.
This relationship, which would appear to be counterintuitive, is likely
under-appreciated by clinicians and clinical pharmacologists.
Drugs that may impact SU were not important factors in the final PKPD
model. This contrasts with other studies that clearly demonstrated that
people taking diuretics have a 25-30% lower oxypurinol clearance
compared to those not taking diuretics.26,27,29 We did
not observe this relationship in our study, likely due to our modest
count of participants (n=4) who were taking various diuretics
(hydrochlorothiazide, triamterene/hydrochlorothiazide, furosemide, and
bumetanide). The association of loop, thiazide, and thiazide-like (but
not potassium-sparing) diuretics with the increased SU and the higher
incidence of gout are well demonstrated from clinical
observations54-57 and in vitrostudies58-60 by inhibiting urate efflux transporters,
such as MRP4 (ABCC4 ) 59 and NPT1
(SLC17A1 )60, or by increasing urate
reabsorption due to extracellular fluid volume deletion from
diuresis.58 On the other hand, the evidence of how
diuretics impact the PK of oxypurinol is less clear, although previous
studies showed loop diuretics, particularly furosemide, to be associated
with increased plasma oxypurinol concentration.51,61Despite not being statistically significant, we found that patients
taking HMG-CoA reductase inhibitors were associated with 52% decrease
in oxypurinol CL/fm . The majority of the
participants were taking atorvastatin (4/5, 80%), which suggests the
potential impact of atorvastatin on the clearance of
oxypurinol.41,42
SLC22A12 rs505802C>T was found to be a key
determinant of oxypurinol clearance CL/fm . This
association is plausible because oxypurinol undergoes extensive
reabsorption through URAT1 encoded bySLC22A12 ,62 such that URAT1 dysfunction would
impact the disposition of oxypurinol. Although the association betweenABCG2 rs2231142C>A and SU-lowering response to
allopurinol has been established in GWAS and replicated in other
observational studies,20-23 no studies have shown a
clear association between this SNP (rs2231142) and the PK parameters of
allopurinol or oxypurinol. However, we cannot rule out the importance ofABCG2 rs2231142C>A, particularly in patients with
extrarenal underexcretion hyperuricemia. Since a larger portion of the
GOUT-H Hmong participants were overproduction hyperuricemia, instead of
extrarenal underexcretion hyperuricemia,25 the impact
of ABCG2 rs2231142C>A may be diminished in our study
population.
An interesting finding was the impact of PDZK1rs12129861G>A on IC50 in the
inhibitory Emax model of oxypurinol. PDZK1 is a key
component of urate-transporting molecular complex for URAT1 and
OAT4.63,64 The PDZK1 rs12129861 A allele was
also associated with a lower SU level24 and a decrease
risk of gout.65,66 We found individuals with AA
genotype have almost half of the IC50 as GG
genotype (8.1 versus 17.6 mg/L) suggesting a higher affinity of
oxypurinol with individuals with AA genotype. However, since this SNP is
in the upstream region of PDZK1 , a causal SNP has yet to be
determined; a mechanistic study needs to be performed to elucidate the
impact of PDZK1 on oxypurinol SU-lowering effect.