Topiloric
Topiloric Uses, Dosage, Side Effects, Food Interaction and all others data.
Topiloric is a selective xanthine oxidase inhibitor developed for treatment and management of hyperuricemia and gout. Xanthine oxidase, or xanthine oxidoreductase (XOR), regulates purine metabolism, and inhibition of the enzyme results in efficacious reduction of serum urate levels. Xanthine oxidase inhibitors are classified into two groups; purine analogs such as Allopurinol and Oxypurinol, and non-purine agents which includes topiroxostat. While Allopurinol is considered a first-line therapy in treating hyperuricemic conditions, it is often associated with side effects and ineffective in reducing uric acid levels under recommended dosing regimens. Renal complications are major comorbidities that limit the Allopurinol therapy as dose reductions are recommended. Topiloric and its metabolites are shown to be unaffected by renal complications, thus may be effective in patients with chronic kidney diseases . Approved for therapeutic use in Japan since 2013, topiroxostat is marketed under the name Topiloric and Uriadec and is orally administered twice daily.
Topiloric reduces the synthesis of uric acid by competitively inhibiting xanthine oxidase in a selective and time-dependent manner . It serves to reduce the concentration of insoluble urates and uric acid in tissues, plasma and urine. Topiloric is not reported to cause QT prolongation .
| Trade Name | Topiloric |
| Generic | Topiroxostat |
| Topiroxostat Other Names | Topiroxostat |
| Type | |
| Formula | C13H8N6 |
| Weight | Average: 248.2428 Monoisotopic: 248.081044286 |
| Protein binding | The mean protein binding of radiolabeled (14C)-topiroxostat in human plasma is >97.5% at 20ng/mL, 98.8% at 200ng/mL, and 98.4% at 2000ng/mL. Binding to serum albumin is most predominant with 92.3-93.2%, and mean protein binding to α1-acid protein and γ-globulin is 12.3% to 16.8% and 34.7% to 40.4%, respectively . |
| Groups | Experimental |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Indicated for the treatment of gout and hyperurcemia in Japan.
How Topiloric works
Uric acid synthesis depends on the action of xanthine oxidase activity in the conversion of hypoxanthine to xanthine, followed by the conversion of xanthine to uric acid. Xanthine oxidase consists of a molybdenum ion as cofactor in the active center that has different redox states upon substrate binding . When a substrate such as hypoxanthine or xanthine binds, xanthine oxidase hydroxylates it and molybdenum ion is reduced from hexavalent, Mo(VI), to tetravalent form, Mo(IV). Molybdenum ion is reoxidized into hexavalent state once the hydroxylated substrate, xanthine or uric acid, dissociates from the active site. Topiloric is shown to interact with multiple amino acid residues of the solvent channel and additionally forms a reaction intermediate by covalent binding with molybdenum (IV) ion via an oxygen atom . It also forms hydrogen bonds with molybdenum (VI) ion, suggesting that it has multiple inhibition modes to xanthine oxidase . Enhanced binding interactions to xanthine oxidase achieves delayed dissociation of topiroxostat from the enzyme. 2-hydroxy-topiroxostat, the metabolite formed by primary hydroxylation of topiroxostat by xanthine oxidase, also causes time and concentration-dependent inhibition of the enzyme . Topiloric is shown to inhibit ATP-binding cassette transporter G2 (ABCG2) in vitro, which is a membrane protein responsible for recovering uric acid in the kidneys and secreting uric acid from the intestines .
Toxicity
Topiloric is not reported to be carcinogenic, genotoxic, or teratogenic . Some reported adverse events of topiroxostat therapy include nasopharyngitis, pain in extremity, elevated alanine aminotransferase (ALT), decreased white blood cell count, eczema and gout arthritis. The no-observed-adverse-effect-level (NOAEL) was determined to be ≥300 mg/kg/day in a study of once-daily, 52-week oral administration of 0/10/30/100 mg/kg/day topiroxostat in monkeys .
Volume of Distribution
The distribution of 14C-topiroxostat (20, 200, and 2000 ng/mL) in human blood cells was 6.7% to 12.8% .
Elimination Route
The time to reach peak plasma concentration of 229.9 ng/mL was 0.67 hour following a single oral dose of 20mg topiroxostat . The oral bioavailability in male rats was 69.6% after oral administration of a single dose of 1mg/kg .
Half Life
The mean half life of topiroxostat after a single oral dose of 20mg topiroxostat is 5 hours under fasting condition. The complex of molybdenum (IV)- topiroxostat has an approximate half life of 20.4 hours .
Clearance
The apparent total body clearance rate is 89.5 L/h and the renal clearance rate is 17.4 mL/h following a single oral dose of 20mg topiroxostat .
Elimination Route
Urinary excretion and fecal excretion of radiolabeled topiroxostat are 30.4% and 40.9% of total dose of 1mg/kg administered to rats, respectively. Within 24 h after a single oral administration of 120mg of topiroxostat, the main metabolites of topiroxostat, N-oxide, N1-gluculonide, and N2-gluculonide, are excreted into urine about 4.8, 43.3, and 16.1 % of the dose, respectively. Unchanged topiroxostat and the hydroxide metabolite was 0.1% or less .
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