Febuxostat

Pharmacological properties

uric acid is the final product of purine metabolism in humans and is formed during this reaction: hypoxanthine → xanthine → uric acid. xanthine oxidase is a catalyst for both stages of this reaction. febuxostat is a derivative of 2-arylthiazole. its therapeutic effect is associated with a decrease in the concentration of uric acid in serum by selective suppression of xanthine oxidase. febuxostat is a powerful and selective non-purine xanthine oxidase inhibitor (np-sixo), its inhibition constant (ki) in vitro is 1 nanomole. febuxostat has been shown to significantly inhibit the activity of both the oxidized and reduced forms of xanthine oxidase. in therapeutic concentrations, febuxostat does not affect other enzymes involved in the metabolism of purines or pyrimidines, such as guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase or purinucorlose.

Clinical Efficiency and Safety

Gout. The effectiveness of the drug Adenuric was confirmed in the 3rd phase of three main studies (2 main studies APEX and FACT and an additional study CONFIRMS, described below), including 4101 patients with hyperuricemia and gout. In each of these main trials of the 3rd phase, Adenuric more effectively reduced the serum concentration of uric acid and maintained it at a proper level compared to allopurinol. The primary endpoint for efficacy in both studies was the proportion of patients in whom, over the past 3 months, the serum uric acid concentration did not exceed 6.0 mg / dl (357 μmol / L). In an additional CONFIRMS Phase 3 study, the results of which became available after the first registration of the drug, the primary endpoint for efficacy was the proportion of patients whose serum uric acid concentration did not exceed 6.0 mg / dL at the time of the last visit. These studies did not include patients undergoing organ transplantation (see SPECIAL INSTRUCTIONS).

APEX study. A randomized, double-blind, multicenter study of the effectiveness of febuxostat with the control of placebo and allopurinol phase 3 (Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat - APEX) lasted 28 weeks. A total of 1072 patients were randomized: placebo (n = 134), Adenuric at a dose of 80 mg 1 time per day (n = 267), Adenuric at a dose of 120 mg 1 time per day (n = 269), Adenuric at a dose of 240 mg 1 time per day (n = 134) and allopurinol (at a dose of 300 mg once a day (n = 258) in patients with an initial serum creatinine concentration of 1.5 mg / dl or 100 mg 1 time per day (n = 10) in patients with initial serum creatinine concentration ≤1.5 and ≤2.0 mg / dl). To assess safety, febuxostat was prescribed at a dose of 240 mg (2 times higher than the maximum recommended dose).

The APEX study showed a statistically significant advantage of both treatment regimens Adenuric at a dose of 80 mg 1 time per day and Adenuric at a dose of 120 mg 1 time per day compared with allopurinol at a usual dose of 300 mg (n = 258) / 100 mg (n = 10) in a decrease in serum uric acid concentration of 6 mg / dl (357 μmol / L) (Table 1).

FACT study. Study of the efficacy of the Febuxostat Allopurinol Controlled Trial, FACT 3-phase febuxostat with a 52-week randomized, double-blind, multicenter study. A total of 760 patients were randomized into groups: Adenuric at a dose of 80 mg 1 time per day (n = 256), Adenuric at a dose of 120 mg 1 time per day (n = 251) and allopurinol 300 mg 1 time per day (n = 253).

The FACT study showed a statistically significant advantage of both regimens (Adenuric at a dose of 80 mg 1 time per day and Adenuric at a dose of 120 mg 1 time per day) compared with allopurinol at a usual dose of 300 mg with respect to lowering and maintaining a serum uric acid concentration of 6 mg / dl (357 μmol / L).

In the table. 1 presents the results of the assessment of the primary endpoint of effectiveness.

Table 1. The proportion of patients with a concentration of uric acid in blood serum 6.0 mg / dl (357 μmol / L) at the last three monthly visits

Study	Adenuric in a dose of 80 mg once a day	Adenuric at a dose of 120 mg once a day	Allopurinol 300/100 mg 1 time per day1
APEX (28 weeks)	48% * (n = 262)	65%*, # (n = 269)	22% (n = 268)
FACT (52 weeks)	53% * (n = 255)	62% * (n = 250)	21% (n = 251)
Consolidated Results	51% * (n = 517)	63%*, # (n = 519)	22% (n = 519)

¹Results among patients receiving 100 mg 1 time per day (n = 10: patients with initial serum creatinine concentrations of 1.5 and ≤2.0 mg / dl) or 300 mg 1 time per day (n = 509), during analysis were combined.

* p0.001 compared with allopurinol; ^#p0.001 compared with a dose of 80 mg.

Adenuric quickly reduced the serum concentration of uric acid, and this effect persisted for a long time. A decrease in serum uric acid concentration of 6.0 mg / dl (357 μmol / L) was observed already at the 2nd week of the study and persisted further during treatment.

CONFIRMS study. A randomized controlled trial of phase 3 CONFIRMS lasting 26 weeks was performed to assess the safety and effectiveness of febuxostat in doses of 40 and 80 mg n