Program

PO1-11-12

A Multicentre Open-Label Pharmacokinetic-Pharmacodynamic Study of Febuxostat in Patients with Chronic Gout

[Speaker] Richard Day:1,2,3
[Co-author] Bishoy Kamel:1,2, Garry G Graham:1,2, Kenneth M Williams:1,2, Sophie L Stocker:1,3, Jane E Carland:1,3, Kevin D Pile:4, Louis E Mcguigan:5, Ian J Portek:6, Neil W Mcgill:7
1:Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Sydney, Australia, 2:School of Medical Sciences, University of New South Wales, Sydney, Australia, 3:St Vincent's Clinical School, University of New South Wales, Sydney, Australia, 4:Department of Medicine, Western Sydney University, Sydney, Australia, 5:Department of Rheumatology, Narrabri Hospital, Australia, 6:Department of Rheumatology, St George Hospital, Sydney, Australia, 7:Department of Medicine, University of Sydney, Sydney, Australia

Introduction. There are conflicting data concerning the effect of renal function on the pharmacokinetics and response to febuxostat (Fbx).
Aims. To explore relationships between the concentrations of serum urate (SU) and plasma Fbx in patients with chronic gout and examine the influence of renal function on the plasma concentrations of Fbx and the efficacy of Fbx.
Methods. Baseline demographics including SU and serum creatinine concentrations were collected. Plasma Fbx concentrations and SU were measured at four times during long term treatment with Fbx over the dosage interval (24 h). Data is presented as mean(SD).
Results. Chronic gout patients (20 males, 6 females) were recruited. The duration of Fbx treatment (40-120 mg/day) was 6 weeks to 66 months. Baseline SU and eGFR were 0.59(0.09) mmol/L and 61(24) mL/min, respectively. Fbx 40 (n=8), 80 (n=17) and 120 (n=5) mg/day achieved similar reductions of SU; 0.34(0.09), 0.36(0.11) and 0.31(0.07) mmol/L, respectively. Target SU ≤0.36 and ≤0.30 mmol/L were achieved by 90% (24/26) and 77% (20/26) of patients, respectively, with Fbx doses of up to 120 mg/day. At Fbx 80 mg daily, the reduction in SU was 0.37(0.09) and 0.34(0.13) mmol/L in patients with eGFR <60 (n=9) and ≥60 (n=8) mL/min, respectively. At Fbx dosage of 80 mg daily, trough concentrations of Fbx were significantly higher in patients with eGFR < 60 mL/min (0.17(0.11)) than those with eGFR ≥60 mL/min (0.03(0.01)) (P=0.009). Renal function had no significant effect on peak Fbx concentrations. There was a 50-fold fluctuation in plasma Fbx over 24 h while SU did not fluctuate significantly over this time.
Discussion. Higher trough Fbx concentrations in patients with eGFR <60 mL/ min may be due to the retention of Fbx-glucuronide and the subsequent regeneration of the parent drug. Renal function does not influence the hypouricaemic response to Fbx. We suggest that the small fluctuation in SU over 24 h is due to the long half-life of urate (20-30 h). A larger sample size is required to confirm present results.
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