API Acotiamide Hydrochloride

Acotiamide Hydrochloride More Info

Acotiamide Hydrochloride is a potent and selective acetylcholinesterase (AChE) inhibitor developed for the treatment of functional dyspepsia (FD), a chronic upper-gastrointestinal disorder characterized by post-prandial fullness, early satiety and epigastric pain in the absence of any organic lesion.

1. Chemistry & Formulation

IUPAC name: N-{2-[bis(propan-2-yl)amino]ethyl}-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxamide hydrochloride

Molecular formula: C₂₁H₃₀N₄O₅S · HCl (anhydrous)

Molecular weight: 486.0 g mol⁻¹

Appearance: white to off-white crystalline powder, freely soluble in water and 0.1 N HCl, formulated as 100 mg oral tablets (tri-hydrate, 111.2 mg/tablet; trade-name Acofide®).

2. Pharmacodynamics

Acotiamide reversibly and competitively inhibits both human erythrocyte AChE (IC₅₀ ≈ 1.6 µM) and plasma butyrylcholinesterase, thereby increasing endogenous acetylcholine concentrations at cholinergic synapses of the enteric nervous system.

Gastric prokinetic activity:

– Accelerates impaired fundic accommodation and antral motility

– Shortens gastric half-emptying time (T½) of both solids and liquids in FD patients

– Enhances gastric compliance and sensory threshold, reducing visceral hypersensitivity

Safety profile: poor CNS penetration (log BB ≈ –1.2) minimises centrally mediated cholinergic adverse effects.

3. Pharmacokinetics

Oral bioavailability: ≈ 60 % under fasted conditions; food delays absorption (Tmax 0.75 → 2 h) but does not reduce overall exposure

Distribution: Vd 2.1 L kg⁻¹; plasma protein binding ≈ 30 %

Metabolism: minor hepatic, mainly via CYP3A4-mediated O-demethylation; three inactive metabolites identified

Elimination: renal excretion of unchanged drug accounts for ~80 %; terminal t½ 4–5 h; total plasma clearance ≈ 12 mL min⁻¹ kg⁻¹

Dose proportionality: linear over 50–200 mg; no clinically relevant accumulation at 100 mg t.i.d.

4. Clinical Efficacy

Three pivotal Phase III trials in Japan (n = 1,362 FD patients) demonstrated:

Significant improvement in overall symptom score vs placebo (–0.42, p < 0.001) after 4 weeks

Responder rates for “marked” or “moderate” global improvement: 52 % vs 35 % (NNT ≈ 6)

Sustained benefit through 52-week open-label extension; no tachyphylaxis observed.

5. Indications & Usage

Adults with functional (non-ulcer) dyspepsia—specifically those exhibiting post-prandial distress syndrome (PDS) or epigastric pain syndrome (EPS)—who remain symptomatic despite lifestyle modification.

6. Dosing & Administration

100 mg orally three times daily, taken just before each main meal. No dose adjustment required in mild renal impairment; use with caution in moderate-to-severe renal failure (CrCl < 50 mL min⁻¹).

7. Adverse Effects

Generally well tolerated; incidence of adverse events comparable to placebo (≈ 10 %).

Most common (≥ 1 %): mild transient diarrhoea, nausea, headache, abdominal discomfort.

No clinically significant prolongation of QTc, no relevant drug–drug interactions via CYP inhibition/induction, and no withdrawal syndrome upon discontinuation.

8. Regulatory Status

First approved in Japan (March 2013, Zeria Pharmaceutical / Astellas); European Medicines Agency granted “orphan designation” for gastroparesis (2015); under regulatory review in several Asian markets; not yet FDA-approved in the United States.

9. Research Directions

Ongoing studies investigate acotiamide’s utility in diabetic gastroparesis, post-operative ileus, and as an adjunct to proton-pump inhibitors in refractory gastro-oesophageal reflux disease.

In summary, Acotiamide Hydrochloride is a targeted, enteric-selective cholinesterase inhibitor that offers a mechanistically novel, safe and effective oral therapy for the symptomatic relief of functional dyspepsia.