Ripasudil Hydrochloride Hydrate
Ripasudil hydrochloride hydrate was first approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Sept 26, 2014. It was developed and marketed as Glanatek® by Kowa Pharmaceuticals.
Ripasudil hydrochloride hydrate is the first drug that can inhibit the rho-associated, coiled-coil containing protein kinase (ROCK). It is indicated for the treatment of glaucoma and ocular hypertension.
Glanatek® is available as solution (0.4%) for ophthalmic use, containing 4 mg of free Ripasudil per millimeter, and the recommended dose is one drop twice daily.
Update Date：2016-03-14
- Drug Name：
- Ripasudil Hydrochloride Hydrate
- Research Code：
- K-115
- Trade Name：
- Glanatec®
- MOA：
- Rho kinase inhibitor
- Indication：
- Ocular hypertension; Glaucoma
- Status：
- Approved
- Company：
- Kowa (Originator)
- Sales：
- ATC Code：
Update Date：2015-07-29
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2014-09-26 | Marketing approval | Glanatec | Glaucoma,Ocular hypertension | Solution/ Drops | 0.4% (Eq. 4 mg Ripasudil per mL) | Kowa |
Update Date：2015-09-16
|
Molecular Weight | 395.88 | ||||||||||||
| Formula | C15H18FN3O2S·HCl·2H2O | |||||||||||||
| CAS No. |
223645-67-8 (Ripasudil); 887375-67-9 (Ripasudil HCl Dihydrate); |
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| Chemical Name | 4-Fluoro-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline monohydrochloride dihydrate | |||||||||||||
| Ripasudil （Free Acid/Base）Parameters： | ||||||||||||||
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| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-08-31
Update Date：2016-02-01
Update Date：2016-06-12
Mechanism of Action
Ripasudil hydrochloride hydrate is a selective ROCK inhibitor (ROCK1: IC50 = 0.051 μM, Ki = 0.023 μM; ROCK2: IC50 = 0.019 μM, Ki = 0.037 μM), of which the important downstream effector is Rho guanosine triphosphates (GTP), playing a critical, calcium-independent role in the regulation of the contractile tone of smooth muscle tissues.
Ripasudil hydrochloride hydrate is an “out-flow” drug, which reduces IOP by stimulating aqueous humour drainage through the trabecular meshwork.
Ripasudil hydrochloride hydrate showed no binding affinity for adrenergic receptors, angiotensin II receptors, endothelin receptors, glutamate receptors, histamine receptors, muscarinic receptors, prostanoid receptors, serotonin receptors, Ca2+ and K+ channels, carbonic anhydrase and HMG-CoA reductase at 1 μM.[8]
In Vitro Efficacy
In monkey TM cells:
● Induced retraction and rounding.
● Reduced actin bundles.
In the barrier function of monkey SCE cell monolayers:
● Reduced TEER.
● In the SCE cells: Decreased ZO-1 immunostaining areas.
In Vivo Efficacy
IOP-lowering effects in animals:
● In normal IOP rabbits:
v Reduced IOP in a dose-dependent manner at 0.0625%.
v The maximum IOP reduction at 1 h after instillation.
● In high IOP rabbits:
v Reduced IOP in a dose-dependent manner at 0.4%.
v The maximum IOP reduction at 2 h after instillation.
● In monkeys:
v Reduced IOP in a dose-dependent manner.
v The maximum IOP reduction at 2 h after instillation.
Aqueous humor dynamics in rabbits:
● No effect on aqueous flow rate or uveoscleral outflow.
● Significantly increased outflow facility by 2.2-fold, and reduced IOP.
Update Date：2016-06-12
Absorption of Ripasudil
Exhibited a linear pharmacokinetics in rats after oral administration. The increase in Cmax and AUC in the dose range of 1 to 10 mg/kg appeared to be dose-proportional.
Had high ophthalmic bioavailability in rabbits (95.8%) and low to high in rats (11.7%, 29.2% and 108%) from low to high dose.
Was absorbed rapidly (Tmax = 14.9-25.5 min) in rats after oral administrations, and also rapidly in rabbits (Tmax = 6.26 min) and humans (Tmax = 0.137-0.301 h) after ophthalmic administrations.
Showed a half-life ranging between 0.49-0.73 h in humans, longer than those in rabbits (24.9 min) after ophthalmic administrations.
Had high clearance in rabbits (64.4-109 mL/min/kg) and moderate clearance in rats (35.0 mL/min/kg), in contrast to liver blood flow, after intravenous administrations.
Exhibited an extensive tissue distribution in all species, with apparent volumes of distribution in rats (1620 mL/kg) and rabbits (2800-3130 mL/kg), after intravenous administrations.
[8]. Japan PMDA.
Distribution of Ripasudil
Exhibited moderate plasma protein binding in humans (56.4%-57.5%), but low in dogs (41.8%-43.1%), rabbits (41.2%-41.9%), and rats (35.3%-36.7%).
The blood cell partition was less than 50% in most species, suggesting low penetration into red blood cells. The blood cell partition values in rats increased in a dose-dependent manner. After a single oral dose of 3 mg/kg to male rats, blood cell partition increased in a time-dependent manner.
After a single oral administration of [14C]ripasudil hydrochloride (3 mg/kg) to male rats:
● The drug was widely distributed into most tissues with high levels of the drug observed in the liver, kidneys, urine in bladder, but the radioactivity in the brain was low.
● Radioactivity concentrations were declined to below measureable levels in most tissues at 168 h post-dose.
● No accumulation was observed.
After a single ophthalmic administration of [14C]ripasudil hydrochloride (0.1%) to male rabbits:
● The highest concentrations of [14C]ripasudil radioactivity were found at 0.25 h post-dose, and the highest levels of the drug observed in the iris-ciliary body, kidneys, tear retina, and choroid.
● Radioactivity concentrations were declined to below measurable levels in most tissues at 366 h post-dose.
[8]. Japan PMDA.
Metabolism of Ripasudil
The major metabolite was hydroxylation derivative M1 in human plasma and rabbit cornea, aqueous humor, crystalline lens, but the major metabolites were M5 and M3 in rat plasma. All the metabolites identified in humans could be found in other species.
Aldehyde oxidase was involved in the formation of M1. Ripasudil was metabolized to M2 by CYP3A5 and 3A4, and M4 by CYP3A5, 3A4 and 2C8.
M1 was an active metabolite.
[8]. Japan PMDA.
Excretion of Ripasudil
Was predominantly excreted through urine, with M5 as the major significant compound in rat urine.
The radioactivity in bile was 38.9% of dose in BDC rats.
[8]. Japan PMDA.
Drug-Drug interaction
Ripasudil exhibited inhibitory effect on CYP2D6 with the IC50 = 5.1 μM (without preincubation) and 3.8 μM (with preincubation). In addition, ripasudil showed inhibitory effect on CYP3A4/5 in the pre-incubation group (IC50 = 14 μM). Ripasudil showed aldehyde oxidase inhibitory activity (IC50 = 1.4 μM).
Ripasudil was not an inducer of CYP1A2, 2A6, 2C8, 2C9, 2C19 or 2D6.
[8]. Japan PMDA.
Update Date：2016-06-12
Single-Dose Toxicity
Single-dose toxicity by the oral or intravenous route in mice, rats and dogs:
● Mouse ALD: 122.55 mg/kg (p.o.); ≥20.42 mg/kg (i.v.).
● Rat ALD: 81.70 mg/kg (p.o.) and 20.42 mg/kg (i.v.).
● Dog MTD: <25mg/kg in males; 18 mg/kg in females.
[8]. Japan PMDA.
Repeated-Dose Toxicity
Repeated-dose toxicity studies by the eye-instillation or oral route in rabbits (26 weeks), dogs (up to 13 weeks), monkeys (52 weeks) and rats (4 weeks)
● For rabbits: The NOAEL was 1.0% (BID, o.l.), determined by the 26-week study. There was no mortality at all doses after ocular instillation, and clinical signs included hyperemia of the bulbar and palpebral conjunctiva, and white spots of the lens.
● For dogs: The NOAEL was 2.0% (QID, o.l.) and 7.5 mg/kg/day (p.o.), determined by the 13-week study. There was no mortality after oral administration or ocular instillation, and clinical signs mainly included hyperemia of the bulbar and palpebral conjunctiva and exposure of nictitating membranes.
● For monkeys: The NOAEL was 2.0% (QID, o.l.), determined by the 52-week study. There were mortalities observed.
● For rats: The NOAEL was 10 and 30 mg/kg/day (p.o.) for males and females, determined by the 4-week study. There were mortalities at oral administration of 90 mg/kg/day, and clinical signs included hyperplasia of bile duct, increased BW, and prolonged PT.
[8]. Japan PMDA.
Safety Pharmacology
Both in vitro and in vivo safety pharmacology studies to assess the effects on neurological, cardiovascular, and respiratory system:
● Neurological function: No effect was observed on general behavior or locomotor activity, but redness of the pinna and limbs in 3/4 cases and a transient and mild hypothermia were observed.
● Cardiovascular function: APD50↑ (>0.82 μM); APD70 ↑and APD90↑ (>8.2 μM); Significant reduction on the maximum rate of repolarization (82 μM). The IC50 of hERG potassium current inhibition was 39.5 μM.
● Respiratory function: No effects on respiratory function.
[8]. Japan PMDA.
Genotoxicity
Ripasudil demonstrated no genotoxicity in all assays employed, i.e., Ames, in vitro chromosomal aberration, in vivo rat micronucleus or UDS assay.
[8]. Japan PMDA.
Reproductive and Developmental Toxicity
Fertility and early embryonic development in rats: No effects.
Embryo-fetal development in rats and rabbits:
● For rats: For the maternal: ↑ BWG and ↓food consumption. For the fetal: ↓ Live fetus, ↑ resorptions and post implantation loss, ↓ fetal weights, and high incidence of incompletely ossifications/delayed fetal ossification.
● For rabbits: Continuous convulsions, tachypnea, ↓locomotor activity, partly closed eyes, spasms, salivation, ↑ BW, ↓ food consumption. There was no effect on fetal development.
Pre- and postnatal development in rats:
● For F0: ↓ BWG and ↓ food consumption, related effect on fertility, ↓birth rate, ↑gestation period, no delivery signs, and mortalities in childbirth.
● For F1: Low fetal survival rate and suppressed postnatal development.
Ripasudil could be excreted to milk in lactating rats.
[8]. Japan PMDA.
Carcinogenicity
Conventional carcinogenicity studies were not carried out, but ripasudil was convinced of no carcinogenic potential based on the following evidences:[8]
● Ripasudil and M1 have a profile of rapid transition and elimination through systemic circulation, which indicated no accumulation in tissues.
● Qualitative structure-activity relationship (QSAR, DEREKTM) models gave no structural alert.
● The negative results of in vivo genotoxicity studies got ripasudil less carcinogenic concern, so did no proliferative or precancerous lesion in the 52-week chronic toxicity study.
● Ophthalmic solution of ripasudil hydrochloride hydrate did not cause inflammatory changes around the eyes.
[8]. Japan PMDA.