Topiroxostat
Topiroxostat was approved by Pharmaceuticals Medical Devices Agency of Japan (PMDA) on June 28, 2013. It was co-developed and marketed as Uriadec®/Topiloric® by Sanwa Kagaku Kenkyusho & Fuji Yakuhin.
Topiroxostat is a xanthine oxidase inhibitor. Xanthine oxidase (XO) is a type of enzyme that generates reductive oxygen species, which catalyze the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid. Topiroxostat could reduce the production of uric acid in the body through the inhibition of xanthine oxidase. It is usually used for the treatment of gout and hyperuricemia.
Uriadec®/Topiloric® is available as tablet for oral use, containing 20, 40 or 60 mg of free Topiroxostat. Generally, the recommended initial dose is 20 mg per time orally, twice daily. The maintenance dose is 60 mg per time, twice daily. The maximum dose is 80 mg per time, twice daily.
Update Date：2016-03-24
- Drug Name：
- Topiroxostat
- Research Code：
- FYX-051
- Trade Name：
- Uriadec® / Topiloric®
- MOA：
- Xanthine oxidase inhibitor
- Indication：
- Gout and hyperuricemia
- Status：
- Approved
- Company：
- Fuji Yakuhin (Originator) , Sanwa Kagaku Kenkyusho
- Sales：
- ATC Code：
Update Date：2015-07-29
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-06-28 | Marketing approval | Topiloric | Gout and hyperuricemia | Tablet | 20 mg/40 mg/60 mg | Fuji Yakuhin | |
| 2013-06-28 | Marketing approval | Uriadec | Gout and hyperuricemia | Tablet | 20 mg/40 mg/60 mg | Sanwa Kagaku Kenkyusho |
Update Date：2015-08-27
|
Molecular Weight | 248.24 | ||||||||||||
| Formula | C13H8N6 | |||||||||||||
| CAS No. | 577778-58-6 (Topiroxostat); | |||||||||||||
| Chemical Name | 4-[5-(Pyridin-4-yl)-1H -1,2,4-triazol-3-yl]pyridine-2-carbonitrile | |||||||||||||
| Topiroxostat （Free Acid/Base）Parameters： | ||||||||||||||
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| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-12-03
Update Date：2015-11-25
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2. WO2005009991A1.
3. JP2005041802A.
4. CN104230891A.
5. WO2014017516A1.
6. CN104151297A.
1. CN103724329A.
Update Date：2016-06-07
Mechanism of Action
Topiroxostat competitively inhibited xanthine oxidase (Ki = 5.1 nM), an enzyme involved in purine metabolism.
Topiroxostat inhibited xanthine oxidase (IC50 = 69 nM) to reduced uric acid in the serum by reducing the production of uric acid.
Topiroxostat showed no more than 10% inhibition against other enzymes in purine and pyrimidine metabolism at 100 μM.
Topiroxostat showed no more than 45% inhibition against 30 enzymes and 54 receptors at 100 μM.
[10]. Japan PMDA.
In Vivo Efficacy
Topiroxostat reduced serum urate in hyperuricemia animals:
● In rats: ED50 = 0.94 mg/kg
● In mice: ED50 = 2.6 mg/kg
● In chimpanzees: Reduced 41% at 1 mg/kg
Topiroxostat reduced urate excretion in urine: 24.8% in 0-24 h post-administration.
[10]. Japan PMDA.
Update Date：2016-06-07
Absorption of Topiroxostat
Exhibited a non-linear pharmacokinetics in rats and dogs following oral dosing. The increase in AUC in the dose range of 0.3 to 3 mg/kg appeared to be more than dose-proportional.
Exhibited a linear pharmacokinetics in humans following oral dosing. The increase in AUC appeared to be dose-proportional in the dose range of 40 to 180 mg topiroxostat.
Had a good oral bioavailability in rats (66.9%-69.6%), dogs (59.6%) and monkeys (79.6%).
Was absorbed rapidly (Tmax = 0.25 to 1 h) in rats, dogs, monkeys and humans.
Showed a half-life of 5.13-5.18 h in rats, 3.51 h in dogs and 4.06 h in monkeys after intravenous administration and
4.56-7.49 h in humans after oral administration.
Had a low clearance in rats (0.16-0.21 L/h/kg), moderate in dogs (0.92 L/h/kg) and monkeys (1.59 L/h/kg), compared to liver blood flow. The Cl/F in Japanese and British was 54.6-89.5 L/h and 61.1-118 L/h after oral administration.
The absorption site of topiroxostat was the upper small intestine.
[10]. Japan PMDA.
Distribution of Topiroxostat
Exhibited high plasma protein binding (>96%). Note that topiroxostat was predominantly bound to HSA (>92%) in humans.
Not significantly penetrated into red blood cells, with a binding to RBC of 6.7%-11.4% at the concentration range of 20-2000 ng/mL in humans.
In SD rats and Long Events rats after a single oral dose administration:
● The drug was rapidly and well distributed from blood into most tissues except for brain, and the clearance from these tis- sues was low.
● Relatively higher concentration levels were observed in kidneys, adrenal gland, and liver. However, concentration of skin in male rats was higher than that of females.
● Some accumulation was observed in kidneys and skin, as well as other organs such as liver, muscle and so on.
● In Long Events rats, the tissues of high concentration were pigmented skin, then non-pigmented skin and eyes, and clear- ance was low.
● The concentration of topiroxostat was below the lower limit of quantitation at 168 h post-dose in SD rats, but at 336 h post-dose in Long Events rats.
[10]. Japan PMDA.
Metabolism of Topiroxostat
Was stable in human liver microsomes.
Overall, the parent drug represented the most abundant component in human, rat and dog plasma, with N-glucuronided topir- oxostat (F11741) as the major metabolite in human plasma, N-glucose topiroxostat (F12006) in dog plasma.
UGT1A9 was the major metabolic enzyme.
The major metabolite in human plasma N-glucuronided topiroxostat (F11741) was an active metabolite (1000 times lower than that of the parent drug).
[10]. Japan PMDA.
Excretion of Topiroxostat
Was predominantly eliminated in urine in humans, with the metabolite F11741 as the most significant component in human urine.
Was predominantly eliminated in feces in rats (male) and dogs, with the parent drug as the most significant component in rat (male) feces.
The reabsorption rate of biliary excreted radioactivity was calculated to be approximately 54.2% in BDC rats after intraduo- denal administration.
[10]. Japan PMDA.
Drug-Drug interaction
Had strong inhibition of CYP2C8/9 (IC50 = 19.7 µM) and 2C9 (IC50 = 9.9 µM), weak inhibition of CYP1A1/2 (IC50 = 33.6 µM), 3A4 (IC50 = 47.4 µM) and 2C19 (IC50 = 57.8 µM), but no inhibition of CYP2A6, 2B6, 2D6 and 2E1.
Had no induction of drug-metabolizing CYP enzymes.
Was an inhibitor of OAT3 (IC50 = 1.05 µM), OAT1 (IC50 = 2.85 µM), BCRP (IC50 = 13.7 µM) and OATP1B1 (IC50 = 41.7 µM), and P-gp, OCT2 and OATP1B3 (IC50 >50 µM).
The metabolites F11087 and F11741 had no inhibition of CYP enzymes. The metabolite F12042 had weak inhibition of CYP2C9 (IC50 = 27.6 µM).
The metabolite F11087 was a strong inhibitor of OAT3 (IC50 = 0.626 µM), moderate of OAT1 (IC50 = 7.69 µM), and weak of
OATP1B1, OATP1B3, OCT2, P-gp and BCRP.
The metabolites F11741 and F12042 had no inhibition of transporters including OAT1, OAT3, OATP1B1, OCT2, BCRP and P-gp.
[10]. Japan PMDA.
Update Date：2016-06-07
Single-Dose Toxicity
Single-dose oral administration of topiroxostat in different species:
● Mouse MTD: 2000 mg/kg
● Rat MTD: 750 mg/kg
● Dog MTD: 2000 mg/kg
● Monkey MTD: 2000 mg/kg
[10]. Japan PMDA.
Repeated-Dose Toxicity
Repeated-dose toxicity studies were performed in rats (up to 26 weeks), dogs (up to 13 weeks) and monkeys (up to 52 weeks):
● For rats: The NOAEL was 0.2 mg/kg/day (0.06 × and 0.18 × MRHD for males and females), determined by the 26-week study.
● For dogs: The NOAEL was 10 mg/kg/day, (1.9 × and 2.5 × MRHD for males and females), determined by the 13-week study.
● For monkeys: The NOAEL was 300 mg/kg/day (58.5 × and 124 × MRHD for males and females), determined by the 52-week study.
● The major target organs of toxicity appear consistently to be kidneys.
[10]. Japan PMDA.
Safety Pharmacology
No effects on central nervous system
Cardiovascular system: In vitro studies, shortened APD50 and APD90 as well as slightly reduced RMP and APA, but no hERG inhibition; Mild increase of heart rates in dog study in vivo.
Respiratory minute volume increased at 30 mg/kg in rats.
[10]. Japan PMDA.
Reproductive and Developmental Toxicity
Fertility and early embryo development: The overall NOAEL was 10 mg/kg/day.
Embryo-fetal development:
● In rats, the overall NOAEL was 30 mg/kg/day.
● In rabbits, the NOAEL was 30mg/kg/day (77.4 × MRHD).
Pre- and postnatal development: In rats, the overall NOAEL was 1 mg/kg/day.
Topiroxostat was able to cross the placenta, the concentration ratio of fetus (blood, brain, heart, lungs, kidneys, digestive tract)/maternal (plasma) = 0.04-32.14.
Topiroxostat excreted through milk: Milk/plasma Cmax ratio = 6.5; Milk/plasma AUCinf ratio = 15
[10]. Japan PMDA.
Carcinogenicity
For mice, the NOAELs were 3 and 1 mg/kg/day (2.16 × and 0.89 × MRHD for males and females, respectively).
For rats, the NOAEL was 1 mg/kg/day for females, which was 0.48 × MRHD.
Mammary gland adenocarcinoma in mice carcinogenicity study and papilla angiosarcoma (kidneys), transitional cell carcino- ma (bladder), interstitial cell tumor (testis), C cell adenoma (thyroid), anterior pituitary adenoma (pituitary) in rats carcino- genicity study was species-specific, which may occurs in humans with low possibility.
[10]. Japan PMDA.