The clinical pharmacokinetics and pharmacodynamics of febuxostat

Abstract

Febuxostat lowers serum urate (SU) by inhibiting xanthine oxidoreductase. The data on the effect of renal function on the pharmacokinetics (PK) of febuxostat and the response of SU pharmacodynamics; PD) to febuxostat are limited and discordant. Febuxostat was reported to reduce the fractional clearance of urate (FCU) in healthy and gout subjects after chronic dosing, suggesting an unexpected mode of action. An HPLC method using fluorescence-detection was developed and validated in order to undertake PK-PD investigations. The new HPLC method is a modification and significant improvement of an existing method. The first study examined the PK-PD of a single dose of febuxostat (80 mg) in healthy subjects and the effect on FCU. The nadir of SU was achieved at 22 hours post-dose while the bulk of febuxostat (81%) was eliminated from plasma during the first 9 hours. Thus, the febuxostat-SU relationship over time exhibited a negative hysteresis as the time course of urate decline lagged behind that of febuxostat concentrations. There was no effect of febuxostat on FCU.The second study aimed mainly at examining the dose-concentration-response relationship of febuxostat and the covariates of the absolute reduction in urate in gout patients treated with febuxostat. Renal function was found to influence the trough concentrations of plasma febuxostat but had no effect on the reduction (absolute and percentage) in urate. Febuxostat 40 mg/day achieved a mean reduction in urate of 53%. Higher doses achieved small but clinically necessary additional hypouricaemic effects. Baseline urate and presence of tophi were significant covariates for the absolute reduction in urate. Finally, a population pharmacokinetic model was developed in order to examine the pharmacokinetics of febuxostat in subjects from the above two studies. Renal function had a significant but small effect on the apparent clearance of febuxostat. Body mass index was a significant covariate of the apparent central volume of distribution. Overall, the findings from this thesis provide a greater understanding of the PK-PD of febuxostat in patients with gout and across a range of renal function and confirm that there is no effect of a single dose of febuxostat (80 mg) on FCU in healthy subjects