The impact of genetic variability in urate transporters on oxypurinol pharmacokinetics

Abstract

The genetic determinants of the allopurinol dose-concentration relationship have not been extensively studied. We aimed to clarify what factors, including genetic variation in urate transporters, influence oxypurinol pharmacokinetics (PKs).A population PK model for oxypurinol was developed with NONMEM (version 7.3). The influence of urate transporter genetic variants for ABCG2 (rs2231142 and rs10011796), SLC2A9/GLUT9 (rs11942223), SLC17A1/NPT1 (rs1183201), SLC22A12/URAT1 (rs3825018), SLC22A11/OAT4 (rs17300741), and ABCC4/ MRP4 (rs4148500), as well as other participant factors on oxypurinol PKs was assessed. Data from 325 people with gout were available. The presence of the T allele for ABCG2 (rs2231142) and SLC17A1/NPT1 (rs1183201) was associated with a 24% and 22% increase in oxypurinol clearance, respectively, in univariate analysis. This effect was not significant in the multivariate analysis. In the final model, oxypurinol PKs were predicted by creatinine clearance, diuretic use, ethnicity, and body weight. We have found that genetic variability in the transporters examined does not appear to influence oxypurinol PKs. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Current knowledge suggests that ABCG2 (rs2231142) genotype is associated with reduced allopurinol treatment response, however, the association with plasma allopurinol or oxypurinol concentrations is less clear. Other renal and gut transporters involved with urate handling have not been extensively studied for an association with altered oxypurinol pharmacokinetics (PKs). WHAT QUESTION DID THIS STUDY ADDRESS?Are genetic variants of renal and gut transporters involved with urate handling, including ABCG2 (rs2231142), associated with altered oxypurinol PKs? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The primary finding of this research was that urate transporter genetics did not significantly impact oxypurinol PKs. Whereas ABCG2 (rs2231142) and NPT1 (rs1183201) were associated with increased oxypurinol clearance by 24% and 22%, respectively, in a univariate setting, this effect was not retained in the multivariate How to cite this article: Hishe HZ, Stocker SL, Stamp LK, et al. The impact of genetic variability in urate transporters on oxypurinol pharmacokinetics.

The development and evaluation of dose‐prediction tools for allopurinol therapy (Easy‐Allo tools)

“…We have previously reported that Pacific Peoples have higher oxypurinol clearance, even after adjusting for body weight, kidney function and transporter variants (eg, ABCG2 and ABCC4). 21 The reason for this finding is not clear. Importantly, this work has not demonstrated differences for M aori (Indigenous New Zealanders) people in oxypurinol handing or Note: The doses are expected to achieve target serum urate concentrations <0.36 mmol L À1 in >80% of people with gout.…”

“…A one-compartment pharmacokinetic model has been found to be a good fit for oxypurinol plasma concentrations in previous work. 20,21 Kidney function, body size and diuretic use have been consistently found to predict oxypurinol pharmacokinetics, 20,21 while recent work has additionally identified an ethnicity effect for selfreported Pacific Peoples. 21 On this basis, the recently published pharmacokinetic oxypurinol model from our group 21 was implemented verbatim.…”

“…20,21 Kidney function, body size and diuretic use have been consistently found to predict oxypurinol pharmacokinetics, 20,21 while recent work has additionally identified an ethnicity effect for selfreported Pacific Peoples. 21 On this basis, the recently published pharmacokinetic oxypurinol model from our group 21 was implemented verbatim. No other structural models for oxypurinol pharmacokinetics, nor any additional covariate analyses, were explored.…”

“…The covariates explored for the pharmacodynamic model were restricted to those proposed in previous analyses to influence the urate-lowering response, 9,11,12,20,21 including creatinine clearance (CLcr), estimated using the Cockcroft-Gault equation, 22 diuretic use, ethnicity, body size and ABCG2 (rs2231142) genotype. 10,23 CLcr and body weight were implemented as time-varying covariates.…”

“…The Easy-Allo dosing tools should be viewed in light of some limitations. In theory, given that urate clearance is reported to be lower than oxypurinol clearance (approximately 4-8 mL min À1 vs 16 mL min À1 , respectively), 21,36 a more mechanistically sensible turn-…”