Acotiamide Hydrochloride Hydrate
Acotiamide hydrochloride hydrate was approved by Pharmaceuticals Medical Devices Agency of Japan (PMDA) on March 25, 2013. It was co-developed and marketed as Acofide® by Zeria & Astellas.
Acotiamide hydrochloride is a novel selective acetylcholinesterase (AChE) inhibitor. Acetylcholine is an important neurotransmitter to regulate gastrointestinal motility, and through the inhibition of degradation of acetylcholine, acotiamide produces the improvement of impaired gastric motility and delayed gastric emptying, and consequently the symptoms of functional dyspepsia. It is usually used for the treatment of postprandial fullness, upper abdominal bloating, and early satiation due to functional dyspepsia.
Acofide® is available as film-coated tablet for oral use, containing 100 mg of Acotiamide hydrochloride hydrate. In general, for adults, take 1 tablet at a time, 3 times a day before meals.
Update Date：2016-03-24
- Drug Name：
- Acotiamide Hydrochloride Hydrate
- Research Code：
- YM-443; Z-338
- Trade Name：
- Acofide®
- MOA：
- Peripheral acetylcholinesterase (AChE) inhibitor
- Indication：
- Functional dyspepsia
- Status：
- Approved
- Company：
- Zeria (Originator) , Astellas
- Sales：
- ATC Code：
Update Date：2015-07-29
| Approval Date | Approval Type | Trade Name | Indication | Dosage Form | Strength | Company | Review Classification |
|---|---|---|---|---|---|---|---|
| 2013-03-25 | Marketing approval | Acofide | Functional dyspepsia | Tablet, Film coated | 100 mg of Acotiamide Hydrochloride hydrate | Zeria, Astellas |
Update Date：2015-09-16
|
Molecular Weight | 541.06 | ||||||||||||
| Formula | C21H30N4O5S•HCl•3H2O | |||||||||||||
| CAS No. |
185106-16-5 (Acotiamide); 773092-05-0 (Acotiamide HCl Trihydrate); |
|||||||||||||
| Chemical Name | N-{2-[Bis(1-methylethyl)amino]ethyl}-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino] thiazole-4-carboxamide monohydrochloride trihydrate | |||||||||||||
| Acotiamide （Free Acid/Base）Parameters： | ||||||||||||||
|
||||||||||||||
| *：Calculated by ACD/Labs software V11.02. | ||||||||||||||
Update Date：2015-08-31
Update Date：2015-11-25
1. WO9636619A1 / US5981557A.
1. WO2012077673A1 / US20130253222A1.
2. WO20060022252A1 / US8772528B2.
1. WO9858918A1 / US6197970B1.
2. CN103709191A.
1. CN104045606A.
1. CN103387552A.
Update Date：2016-06-07
Mechanism of Action
Acotiamide, an AChE inhibitor, enhanced acetylcholine (ACh)-induced contraction and motility of the gastric antrum and body.
Acotiamide inhibited human AChE with mixed pattern (Ki1 = 0.61 ± 0.03 µM, Ki2 = 2.7 ± 0.2 µM, and IC50 = 3 µM) and suppressed the degradation of ACh released from cholinergic nerve terminals.
The AChE inhibitory effect of acotiamide almost disappeared by dialysis, which was shown to be reversible.
Acotiamide did not show a high affinity to the muscarinic M1, M2, M3, dopamine D2S and serotonin 5-HT4 receptors involving in the regulation of gastrointestinal motility.
[8]. Japan PMDA.
In Vitro Efficacy
Improved ACh-induced contraction in gastric sample at 1 μM.
Enhanced electrical-induced contraction in gastric sample at 0.3 μM.
[8]. Japan PMDA.
In Vivo Efficacy
Acotiamide significantly improved the gastrointestinal motility:
● In normal and clonidine-induced gastric antrum hypomotility dogs: at 10 mg/kg i.d..
● In normal rats: at 30 mg/kg s.c..
● In clonidine-induced gastric antrum hypomotility rats: at 100 mg/kg, i.d..
Significantly improved the clonidine-induced delay of gastric emptying in rats: at 100 mg/kg, s.c..
Significantly increased gastric juice secretion (acid output) in 2 h post-administration in rats: at 100 mg/kg, s.c..
[8]. Japan PMDA.
Update Date：2016-06-07
Absorption of Acotiamide
Exhibited a linear pharmacokinetics in humans following oral dosing. The increases in Cmax and AUC appeared to be dose-proportional in the dose range of 50 to 800 mg acotiamide.
Had a low oral bioavailability in rats (13.9%-19%) and moderate in dogs (37.5%-50.4%).
Was absorbed rapidly (Tmax = 0.08-3 h) in rats, dogs as well as humans.
Showed a half-life of 10.9-21.7 h in humans, much longer than those in rats (2.1-3.7 h) and dogs (2.5-3.0 h), after oral
administration.
Had a high clearance in rats (4.3 L/h/kg) and dogs (2.1 L/h/kg), compared to the liver blood flow, after intravenous
administration. The Cl/F in humans was 440-823 L/h after oral administration.
Exhibited an extensive distribution in rats, dogs, with apparent volume of distribution at 4.9 and 4.2 L/kg, respectively, after intravenous administration. The apparent volume of distribution in humans was 1.69 L after oral administration.
Showed a low permeability, with a Papp(A→B) of (0.8-1.3) × 10-6 cm/s at 1-500 μM in LLC-PK1 Cells.
[8]. Japan PMDA.
Distribution of Acotiamide
Exhibited moderate plasma protein binding in humans (84%-85%), rats (75%-77%) and dogs (53%-61%).
Had a Cb:Cp ratio of 0.85-0.95 in humans, suggesting moderate penetration into red blood cells.
Albino and pigmented male rats following a single oral administration of acotiamide:
● The drug was rapidly and well distributed into most tissues excluding the central nervous system, with little or no radioactivity in the brain.
● Relatively higher concentration levels were observed in small intestine, stomach, urinary bladder, kidneys, liver, and artery, compared to other organs, at 0.5 h post-dose.
● Radioactivity concentrations decreased below the lower limit of quantification in all tissues at 24 h post-dose.
Pigmented male rats following a single oral administration of acotiamide:
● The radioactivity concentration in the eyeballs was 12% of that in plasma at 0.5 h post-dose, and the concentration remained, albeit at a low level, suggesting the possibility that the drug was distributed in melanin-containing tissues.
● No significant difference was observed in changes over time in the radioactivity concentration in white and pig-mented dermal tissue.
[8]. Japan PMDA.
Metabolism of Acotiamide
Could be metabolized in rat, mouse, rabbit and human liver microsomes, but not detectable in dog liver microsomes.
UGT1A8 and UGT1A9 were the major metabolizing enzymes, with UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A10, UGT2B7 and UGT2B15 involved in the metabolism of acotiamide.
CYP1A1, CYP3A4, CYP2C9, CYP2C8, CYP2C19, CYP2D6, CYP3A5, or CYP4A11 made little contribution to the metabolism of acotiamide.
Overall, the parent drug represented the most abundant component, with the glucuronide conjugate of acotiamide (M1) as the major metabolite in liver microsomes of rat, mouse, rabbit and human except for dogs.
The parent drug and metabolites M2 and M1 were detected in human plasma.
In addition, M1 represented the most abundant component in mouse and rat plasma, while the parent drug in dog plasma.
[8]. Japan PMDA.
Excretion of Acotiamide
Was predominantly eliminated in feces in humans and tested animals, with the parent drug as the most significant component in mouse, rat, dog and human feces.
About 37% of acotiamide was recovered via biliary excretion in bile duct-cannulated (BDC) rats.
The reabsorption rate of biliary excreted radioactivity was calculated to be approximately 7% in BDC rats after intra-duodenal administration.
[8]. Japan PMDA.
Drug-Drug Interaction
Acotiamide did not inhibit or induce most of the CYP enzymes, indicating a low level drug interaction.
Acotiamide was the substrate of P-gp and had weak inhibition of P-gp, with inhibition of 21.1% at 50 μM.
[8]. Japan PMDA.
Update Date：2016-06-07
Single-Dose Toxicity
Single-dose oral administration of acotiamide in different species:
● Rat MTD: 2000 mg/kg
● Dog MTD: 2000 mg/kg
[8]. Japan PMDA.
Repeated-Dose Toxicity
Repeated-dose oral administration of acotiamide in different species from 4 to 39 weeks:
● For rats: The NOAEL was 300 mg/kg/day (29 and 12 × MRHD for males and females, respectively), determined by 26-week study, and no toxicologically significant effect was observed.
● For dogs: The NOAEL was 30 mg/kg/day (6 × MRHD) in males and 100 mg/kg/day (10 × MRHD) in females, de-termined by 39-week study, and these observation resulted from pharmacological action of acotiamide.
[8]. Japan PMDA.
Safety Pharmacology
No apparent toxicity was observed in a standard battery of safety pharmacology studies.
[8]. Japan PMDA.
Genotoxicity
No genetic risk was found in a standard battery of genotoxicity studies.
Very weak positive results were found in chromosomal aberration study in CHL.
[8]. Japan PMDA.
Reproductive and Developmental Toxicity
Fertility toxicity: The NOAEL was 1000 mg/kg/day for both male and female rats.
Embryo-fetal development toxicity: The NOAEL for maternal was 300 mg/kg/day (13 × MRHD) in rats and 100 mg/kg/day (2.2 × MRHD) in rabbits. The NOAEL for fetus was 1000 mg/kg/day (19 × MRHD) in rats and 300 mg/kg/day (24 × MRHD) in rabbits.
Pre- and postnatal developmental toxicity: The NOAEL was determined as 1000 mg/kg/day for F0 and F1 in rats. Acotiamide can be transferred through placenta and excreted through milk.
[8]. Japan PMDA.
Carcinogenicity
Increased incidence of endometrial adenocarcinoma was found in 2-year rat tests, but not in rasH2 transgenic acceler-ating tests.
[8]. Japan PMDA.