Fasudil Hydrochloride Hydrate

Fasudil hydrochloride Hydrate was approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on June 30, 1995. It was developed and marketed as Eril^® by Asahi Kasei in Japan.

Fasudil hydrochloride is a selective RhoA/Rho kinase (ROCK) inhibitor. ROCK is an enzyme that plays an important role in mediating vasoconstriction and vascular remodeling in the pathogenesis of PH. ROCK induces vasoconstriction by phosphorylating the myosin-binding subunit of myosin light chain (MLC) phosphatase, thus decreasing MLC phosphatase activity and enhancing vascular smooth muscle contraction. Eril^® is indicated for the treatment of cerebral vasospasm and cerebral ischemia.

Eril^® is available as injection for intravenous use, containing 30 mg of Fasudil hydrochloride. The recommended dosage is 30 mg fasudil hydrochloride should be diluted in 50-100 mL solution and administered by intravenous infusion over 30 minutes 2-3 times daily.

Index：

General Information

Update Date：2016-04-13

Drug Name：: Fasudil Hydrochloride Hydrate
Research Code：: AT-877; HA-1077
Trade Name：: Eril^®
MOA：: Rho kinase inhibitor
Indication：: Brain ischemia; Cerebral vasospasm
Status：: Approved
Company：: Asahi Kasei (Originator)
Sales：: $16.5 Million (Y2011)
ATC Code：: C04AX32

Approved Countries or Area

Update Date：2015-07-29

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
1995-06-30	First approval	Eril	Cerebral vasospasm,Brain ischemia	Injection	Eq. 30 mg Fasudil Hydrochloride	Asahi Kasei

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2013-08-29	Marketing approval		Cerebral vasospasm,Brain ischemia	Injection	30 mg/2 mL	广州白云山明兴制药	6类
2013-04-12	Marketing approval		Brain ischemia,Cerebral vasospasm	Injection	30 mg/2 mL	江苏迪赛诺制药	6类
2013-04-12	Marketing approval		Cerebral vasospasm,Brain ischemia	Injection	30 mg/2 mL	安徽恒星制药	6类
2011-05-31	Marketing approval		Cerebral vasospasm,Brain ischemia	Injection	30 mg/2 mL	成都苑东药业	6类
2010-04-19	Marketing approval	依立卢/Eril	Cerebral vasospasm,Brain ischemia	Injection	30 mg/2 mL	Asahi Kasei

Chemical Structure

Update Date：2015-12-08

Molecular Weight

336.84

Formula

C14H17N3O2S・HCl・1/2H2O

CAS No.

103745-39-7 (Fasudil);
186694-02-0 (Fasudil HCl Semihydrate);

Chemical Name

hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine monohydrochloride hemihydrate

Fasudil （Free Acid/Base）Parameters：

MW	H_D	H_A	FRB^*	PSA^*	cLogP^*
291.37	1	5	2	70.7	1.716±0.638

^*：Calculated by ACD/Labs software V11.02.

Synthesis & Impurities

Update Date：2015-09-22

Route 1

Reference：

1. US4678783A / EP0187371B1.

2. CN102020636A.

Impurity database is being updated！

Non-clinical Pharmacology

Update Date：2016-06-12

Mechanism of Action

Fasudil hydrochloride hydrate is a potent inhibitor of Rho kinase (Ki = 0.40 ± 0.03 μM). The Rho GTPase is involved in such diverse biological processes as smooth muscle contraction, cell adhesion and cell growth.

Fasudil hydrochloride hydrate has effected on contractile responses to various agonists which were examined on strips of rabbit aorta. The concentration-response curves to 5-HT, PGF2a, histamine, Ang II, DA and NA were concentration-dependently shifted to the right (0.3-3.0 μM).

Reference：

[3]. Am J Physiol Cell Physiol 2000, 278, C57-65.

[4]. Br J Pharmacol 1989, 98, 1091-1100.

[5]. Br J Pharmacol 2000, 130, 219-230.

[6]. Life Sciences 2001, 69, 1441-1453.

[7]. Jpn. J. Pharmacol 1999, 80, 41-44.

[8]. Brain Res. Bull. 2011, 84, 174-177.

[9]. Stroke 2000, 31, 2245-2250.

[10]. Br. J. Pharmacol. 1996, 118, 1592-1596.

[11]. J. Clin. Neurosci. 1999, 6, 394-399.

[12]. Life Sciences 2000, 67, 1929-1939.

In Vitro Efficacy

Inhibitory effects of fasudil on contractions produced by different types of stimuli:

● Posterior cerebral artery of rats: IC₅₀ = 4.8 μM (pressure), 4.9 μM (KCl) or 6.9 μM (U46619)

● Basilar artery of dogs: IC₅₀ = 9.8 μM (KCl), 3.3 μM (PGF2α) or 5.6 μM (U46619)

● Middle cerebral artery of dogs: IC₅₀ = 3.5 μM (KCl) or 2.9 μM (PGF_2α)

Efficacy of fasudil in cells:

● Chemotaxis of neutrophil: MED = 3-30 μM

● MLC phosphorylation in neutrophil: MED = 1 μM

● Neurite retraction of NIE-115 cell: MED = 1.7 μM

Reference：

[3]. Am J Physiol Cell Physiol 2000, 278, C57-65.

[4]. Br J Pharmacol 1989, 98, 1091-1100.

[5]. Br J Pharmacol 2000, 130, 219-230.

[6]. Life Sciences 2001, 69, 1441-1453.

[7]. Jpn. J. Pharmacol 1999, 80, 41-44.

[8]. Brain Res. Bull. 2011, 84, 174-177.

[9]. Stroke 2000, 31, 2245-2250.

[10]. Br. J. Pharmacol. 1996, 118, 1592-1596.

[11]. J. Clin. Neurosci. 1999, 6, 394-399.

[12]. Life Sciences 2000, 67, 1929-1939.

In Vivo Efficacy

The effect of fasudil on animal models:

● Cerebral microthrombosis rat model: Neurological deficits were significantly improved and the infarct area re-duced.

● Middle cerebral artery occlusion rat model: Blood viscosity and hematocrit were significantly decreased.

● Normal mongrel dog model: MBP was dose-dependently decreased, and HR, VBF, CBF, RBF and FBF increased.

● Subarachnoid haemorrhage dog model: Both endothelial damage and neutrophil infiltration were inhibited.

Reference：

[3]. Am J Physiol Cell Physiol 2000, 278, C57-65.

[4]. Br J Pharmacol 1989, 98, 1091-1100.

[5]. Br J Pharmacol 2000, 130, 219-230.

[6]. Life Sciences 2001, 69, 1441-1453.

[7]. Jpn. J. Pharmacol 1999, 80, 41-44.

[8]. Brain Res. Bull. 2011, 84, 174-177.

[9]. Stroke 2000, 31, 2245-2250.

[10]. Br. J. Pharmacol. 1996, 118, 1592-1596.

[11]. J. Clin. Neurosci. 1999, 6, 394-399.

[12]. Life Sciences 2000, 67, 1929-1939.

Non-clinical Pharmacokinetics

Update Date：2016-06-12

Absorption of Fasudil

Was absorbed rapidly (T_max = 0.5 h) in humans.

Showed a short half-life (0.3 h) in humans, similar to that in rats (0.48 h), after intravenous administration.

Reference：

[6]. Life Sciences 2001, 69, 1441-1453.

[13]. J. Biol. Chem. 2000, 275, 10168-10174.

Distribution of Fasudil

Not available

Reference：

[6]. Life Sciences 2001, 69, 1441-1453.

[13]. J. Biol. Chem. 2000, 275, 10168-10174.

Metabolism of Fasudil

M3 was an active metabolite.

Reference：

[6]. Life Sciences 2001, 69, 1441-1453.

[13]. J. Biol. Chem. 2000, 275, 10168-10174.

Excretion of Fasudil

Not available

Reference：

[6]. Life Sciences 2001, 69, 1441-1453.

[13]. J. Biol. Chem. 2000, 275, 10168-10174.

Drug-Drug interaction

Not available

Reference：

[6]. Life Sciences 2001, 69, 1441-1453.

[13]. J. Biol. Chem. 2000, 275, 10168-10174.

Non-clinical Toxicology

Update Date：2016-06-12

Single-Dose Toxicity

LD₅₀ were established by varied administration route in mice, dogs and monkeys.

Reference：

[14]. Japan PMDA.

Repeated-Dose Toxicity

The major organ lesion is renal failure. Besides, reflections on nervous system included drooling in CNS and spasm in ANS

Reference：

[14]. Japan PMDA.

Safety Pharmacology

Neurotoxicity related to fasudil included convulsions, low spontaneous momentum, suppression of coordination and slackness of nictitating membrane.

The major cardiovascular observation of fasudil was elevated blood pressure.

Adverse effects on GI tract was inhibition of gastrointestinal peristalsis.

Reference：

[14]. Japan PMDA.

Genotoxicity

Not conducted.

Reference：

[14]. Japan PMDA.

Reproductive and Developmental Toxicity^[14]

Fertility and early embryonic development

● Inhibited ovulation was found in females.

Embryo-fetal development

● No essential adverse effects.

Perinatal toxicity

● Body weight gain of F1 generation decreased, but fertilities were not affected.

Reference：

[14]. Japan PMDA.

Carcinogenicity

Not conducted.

Reference：

[14]. Japan PMDA.