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.