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.