Dr FARAZ FARISHTA Consultant Endocrinologist Medwin Hospital MD Of Sparsh Endocrinology &Diabetic

centersPresident of Diabetes Awareness Foundation

Hyperurecemia & Role of Febuxostat

Gastro-intestinal system

Uric acid is the normal end product of the degradation of purine* compounds.

Major route of disposal is renal excretion .

Humans lack the enzyme uricase to break down uric acid into more soluble form.

Metabolic Disorder underlying gout is Hyperuricemia (high levels of uric acid in blood).

Uric acid & Hyperuricemia:

Gastro-intestinal system Urates

• The ionized forms of uric acid, predominant in plasma, extracellular fluid and synovial fluid.

• Approximately 98% exists as monosodium urate at pH 7.4

• Plasma is saturated with monosodium urate at a concentration of 6.8 mg/dl.

• At higer concentrations, plasma is therfore supersaturated, creating the potential for

urate crystal precipitation.

• 2/3 rd to 3/4 th of urate is excreted by kidneys, and most of the remainer is eliminated through the intestines.

Gastro-intestinal systemHyperuricemia

Can result from:

Increased production of uric acid

Decreased excretion of uric acid

Combination of the two processes.

Gastro-intestinal system

• Uric acid overproduction

Accounts for 10% of hyperuricemiaDefined as 800mg of uric acid excreted

• Uric acid underexcretion

Accounts for >90% of hyperuricemiaDiminished tubular secretory rate, increased tubular reabsorption, diminished uric acid filtration

Classification of Hyperuricemia

Gout is a form of arthritis which causes inflammation and pain

in the joints.

Mostly the joints of the lower body are

affected.

Gout develops due to uric acid crystals forming deposits

in the body.

The best and most effective gout cure is a proper balanced diet.

Meats such as beef,poultry,lamb,andpork contain high levels of purine

You should also avoid organ meats such as liver and kidney .

Foods that people with gout should avoid

Gastro-intestinal systemVarious Treatments

• NSAIDs Most commonly used. No NSAID found to work better than others• Colchicine

• Corticosteriods Patients who cannot tolerate NSAIDs, or failed

NSAID/colchicine therapy

• Xanthine oxidase inhibitors

Gastro-intestinal system

Febuxostat

• New class of Xanthine Oxidase inhibitor

• More selective than allopurinol

• Little dependence on renal excretion

• Xanthine oxidase inhibitors

Gastro-intestinal system

Febuxostat is a selective inhibitor of Xanthine Oxidase and is indicated for use in the treatment of Hyperuricemia and Gout.

Xanthine oxidase generates reactive oxygen species and is an enzyme that catalyzes the formation of uric acid.

Febuxostat received Marketing approval by the European Medicines Agency on April 21, 2008.

Febuxostat was approved by the US FDA on February 16, 2009.

Febuxostat

Gastro-intestinal systemPurine nucleotides

Hypoxanthine

Xanthine

Uric acid

Xanthine oxidase

Alimentary excretion

Urinary excretionTissue deposition in excess

Urate crystal Microtophi

Phagocytosis with acute inflammation and arthritis

Uricosurics

ColchicineNSAID

Febuxostat

Mechanism of Action

Febuxostat

Gastro-intestinal system

FEBUXOSTAT ALLOPURINOL

• Non-purine structure. •Purine analog.

• Selective Inhibitor of xanthine oxidase. It does not inhibit other enzymes involved in purine/ pyrimidine synthesis and metabolism.

• Inhibitor of xanthine oxidase. May inhibit other enzymes involved in purine/pyrimidine synthesis and metabolism.

• Both hepatic and renal elimination. Thus can be given safely in mild to moderate renal / hepatic patients.

• Eliminated primarily via renal excretion. Thus can’t be given safely to renally impaired patients.

• Requires no dose adjustment in patients with mild to moderate renal or hepatic impairment.

• Requires dose adjustment in patients with renal impairment.

Febuxostat V/s Allopurinol

Gastro-intestinal system

FEBUXOSTAT ALLOPURINOL

The dosing is 40–mg or 80-mg tablets. Thus, lesser Dose Dumping and lesser dose-related toxicity (if any).

The dosing is 100-mg or 300-mg tablets. Thus, greater Dose Dumping and greater dose-related toxicity (if any).

Recommended starting dose is 40 mg. The minimal effective dosage is 100 mg daily.

For patients who do not achieve a serum uric acid level of < 6mg/dl after 2 weeks, FEBUXOSTAT80 mg is recommended.

It is recommended the patient start with 100 mg daily and increase at weekly intervals by 100 mg until a serum uric acid level of < 6 mg/dl is attained.

DOSE ADVANTAGES

Gastro-intestinal systemFebuxostat… Role in T2DM

• Febuxostat is effective at lowering uric acid levels.

• Resulting into improved Nitric oxide production.

• Helps to decrease insulin resistance and the progression of T2DM.

• Low dose with comparable (Allopurinol) decrease in serum uric acid level.

• A novel therapy that helps in reducing pain associated with hyperuricemia and increases mobility.

Gastro-intestinal system

The superior potency for inhibition of endothelium-associated

XO is predictive of a significant role for Febuxostat. - FreeRadicBiol Med.2011 Jul

1;51(1):179-84.

Febuxostat … Role in Hypertension

Hypertension

Uric acid/Hyperuricemia

Endothelium dysfunction

Elevates

Linke

d Nitric oxide

Redu

ces

Febuxostat

Gastro-intestinal systemFebuxostat … Role in CKD

• Febuxostat, by inhibiting xanthine oxidase, can decrease uric acid production, thus decreasing the incidence of urolithiasis.2

• 2. In a subset of patients with stage 2 to 3 CKD, febuxostat 40 and 80 mg daily were also superior in achieving the serum urate target level in comparison to renally dose-adjusted allopurinol (200 to 300 mg daily)1.

• 3. 80 mg febuxostat dose does not require adjustment in CKD3

• 4. In patients with gout and preexisting mild to moderate renal impairment, febuxostat is more effective and as safe as allopurinol.4

• 5. In preexisting renal impairment, febuxostat is highly

effective, and as safe as allopurinol.

1-Arthritis Research & Therapy. 2009;11(4):236 , 2-Clinical Medicine Insights: Therapeutics 2010:2 , 3-Int J Nephrol Renovasc Dis. 2010; 3: 1–10. 4,5- Medpage:Pub Nov: 02, 2009

Gastro-intestinal system

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APEX (6 Months) FACT (1 Year) CONFIRMS (6 Months)

Febuxostat (80 mg)

Allopurinol (300 mg)

APEX study (6 months):• 72% of patients on Febuxostat (80 mg) reached a healthy uric acid level.• 39% of patients on Allopurinol (300 mg) reached a healthy uric acid level.

FACT study (1 year):• 74% of patients on Febuxostat (80 mg) reached a healthy uric acid level.• 36% of patients on Allopurinol (300 mg) reached a healthy uric acid level.

CONFIRMS study (6 months):• 67% of patients on Febuxostat (80 mg) reached a healthy uric acid level.• 42% of patients on Allopurinol (300 mg) reached a healthy uric acid level.

Febuxostat Vs. Allopurinol.

Gastro-intestinal system

• Greater proportion of Febuxostat-treated patients have decreased size and number of tophi.

• A greater percentage of patients receiving Febuxostat versus Allopurinol

achieved complete resolution of tophi.

• Thus, the reduction in serum uric acid level is greater with Febuxostat and is higher when compared to Allupurinol.

• Moreover, the reoccurrence of uric acid level in blood is significantly less with Febuxostat treatment when compared to Allupurinol.

Observations : Febuxostat in comparision to Allopurinol …

Gastro-intestinal system

• Non-purine, Selective Xanthine Oxidase inhibitor.

• Powerfully lowers serum uric acid to target levels of < 6 mg/dL.

• Can be safely prescribed to patients with mild to moderate renal impairment.

• Efficacious in patients with high baseline serum uric acid levels >10mg /dl.

• Febuxostat is superior to Allopurinol in patients with mild to moderate renal dysfunction.

• Can be safely prescribed to patients poorly controlled on Allopurinol.

• Maintains Serum Uric Acid levels <6 mg / dl even in Allopurinol intolerant patients.

Take Home Message Foxstat

Gastro-intestinal system

Thank you