What is the mechanism of action (MOA) of Febuxostat (febuxostat)?

Mechanism of Action of Febuxostat

Febuxostat is a non-purine selective inhibitor of xanthine oxidase that reduces serum uric acid production through potent and selective inhibition of the enzyme xanthine oxidase. 1, 2

Pharmacological Properties

• Febuxostat selectively inhibits xanthine oxidase/xanthine oxidoreductase, the enzyme responsible for converting hypoxanthine to xanthine and xanthine to uric acid in the purine metabolism pathway 2, 3
• Unlike allopurinol (which is a purine analog), febuxostat has a non-purine structure that provides selective inhibition of xanthine oxidase with minimal effects on other enzymes involved in purine and pyrimidine metabolism 2, 4
• The selective nature of febuxostat's inhibition contributes to its efficacy in lowering serum uric acid levels 3, 5

Pharmacokinetic Properties

• Febuxostat has high oral bioavailability of approximately 85% 5
• The drug follows a two-compartment model with an initial half-life of approximately 2 hours and a terminal half-life of about 9.4 hours 5
• Febuxostat is extensively metabolized in the liver through oxidation (approximately 35%) and acyl glucuronidation (up to 40%) 5
• The acyl glucuronide metabolites are primarily cleared by the kidneys 5
• Unlike allopurinol, febuxostat does not require dosage adjustment in patients with mild to moderate renal impairment 4, 5

Clinical Efficacy

• Febuxostat rapidly and sustainably reduces serum uric acid levels by 25-70% in both uric acid underexcretors and overproducers 3
• Clinical studies have demonstrated that febuxostat 80 mg/day is more effective than allopurinol 300 mg/day at decreasing serum urate levels 1, 4
• Febuxostat is particularly effective in patients with moderate to severe renal impairment (eGFR <60 ml/min) 1, 6
• The drug maintains target serum urate levels (<6 mg/dL) in most patients during long-term treatment 4

Clinical Applications

• Febuxostat is indicated for the treatment of chronic hyperuricemia in patients with gout where urate deposition has already occurred 1
• It is particularly useful in patients with recurrent gout flares, tophi, urate arthropathy, or uric acid renal stones 1
• Febuxostat can be considered when allopurinol is not tolerated or contraindicated, especially in patients with a history of allopurinol hypersensitivity syndrome 1
• It is available in 40 mg and 80 mg doses, with treatment typically initiated at 40 mg/day and titrated as needed to achieve target serum urate levels 1

Important Considerations

• Febuxostat carries an FDA black box warning regarding cardiovascular risk; the American College of Rheumatology conditionally recommends switching to an alternative urate-lowering therapy for patients taking febuxostat with a history of cardiovascular disease or new cardiovascular events 1, 6
• The most common adverse reactions associated with febuxostat include liver function abnormalities, nausea, arthralgias, and rash 2, 7
• Prophylaxis against acute gout flares should be provided when initiating febuxostat, typically with colchicine or low-dose NSAIDs if not contraindicated 1, 6
• Febuxostat has a drug interaction with xanthine oxidase inhibitors like allopurinol, which can lead to severe, life-threatening myelotoxicity 8