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Abstract
Hyperuricaemia (serum urate (SU) concentrations ≥ 0.42 mmol/L) is the most important risk factor for gout, a common form of inflammatory arthritis. First choice treatment for gout is the xanthine oxidoreductase (XOR) inhibitor, allopurinol. Febuxostat recently became the second member of this class. Unfortunately, current treatment practices are suboptimal and the prevalence of gout and hyperuricaemia is increasing. The overall aim of the thesis was to examine risk factors for hyperuricaemia and to investigate methods to optimise XOR treatment for gout.
The first study aimed to explore the relative influences of factors that increase the risk of hyperuricaemia. Renal, extra-renal, dietary and metabolic factors and male sex were discovered to strongly contribute to the risk of hyperuricaemia. Importantly, no association was found between the fractional clearance of urate and the ABCG2 Q141K genotype, each a marker of renal and intestinal clearance pathways, respectively. Reduced intestinal clearance of urate has a much greater risk of causing hyperuricaemia than previously conceived.
The second study aimed to analyse the dose- and concentration-response relationships of allopurinol and its active metabolite, oxypurinol, with SU concentration. An allopurinol dose-response model incorporating a ‘resistant’ concentration of SU adequately described the urate-lowering effect of allopurinol. The dose required to reach a target SU concentration was dependent on the baseline SU concentration but not renal function. From this, a novel nomogram was developed to individualise allopurinol dosage.
The final study aimed to examine the dose-response relationship of febuxostat with SU concentration.
Again, analogous to the finding with allopurinol, the dose of febuxostat required to reach target SU
concentration was dependent on the baseline SU concentration. By contrast with allopurinol, renal function was an influential covariate that significantly improved this relationship. A ‘resistant’ concentration of SU for febuxostat was identified but was lower than that for allopurinol. As the ‘resistant’ concentration of SU identified in both models lie below the clinical target SU concentration, there is unlikely to be a clinically meaningful difference between these drugs.
Overall, the findings from this thesis provide a greater understanding of the mechanisms of hyperuricaemia and how we can individualise XOR inhibitor therapies to optimise treatment of gout.