Acofide Mechanism of Action

ATC Code: A03FA10.
Pharmacology: Pharmacodynamics: Mechanism of action: Acofide demonstrated an action to inhibit acetylcholinesterase (in vitro).
Gastroprokinetic action: Acofide enhanced postprandial gastric antral motility in dogs and gastric antral motility in rats.
Acofide also improved clonidine-induced gastric antral hypomotility in dogs and rats.
Improvement effect on delayed gastric emptying: Acofide improved clonidine-induced delayed gastric emptying in rats.
Clinical Studies: Phase III study: The results of a double-blinded comparative clinical study in patients with functional dyspepsia^{Note 1)} whose main symptoms were postprandial fullness, upper abdominal bloating, and early satiation were as follows. When one tablet of this product (100 mg as acotiamide hydrochloride hydrate) was administered orally before meals three times daily for 4 weeks, superiority to the placebo group was examined for the two primary endpoints: improvement rate of the subjects' impression and resolution rate of three symptoms (postprandial fullness, upper abdominal bloating, and early satiation). The results on the two endpoints changed over time during the 4-week treatment period and 4-week post-treatment observation period are as presented in the figures as follows.
Note 1) Patients aged 20 to 64 years who have presented with at least one of the three symptoms (postprandial fullness, upper abdominal bloating, and early satiation) according to the Rome III criteria for at least 6 months before informed consent, and the symptom(s) have persisted for at least 3 months before informed consent. (See Tables 1 and 2, Figure 1, Table 3, Figure 2 and Table 4.)

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The incidence rate of adverse drug reactions was 16.9% (76/450) for the 300 mg/day group and 18.1% (80/442) for the placebo group. The major adverse drug reactions were blood prolactin increased (3.6%, 16/450) and ALT increased (1.8%, 8/450) in the 300 mg/day group and blood prolactin increased (4.8%, 21/442) and diarrhea (2.3%, 10/442) in the placebo group. [See Important precautions under Precautions.]
Long-term administration study: In the long-term treatment study which set duration of the treatment to at least 24 weeks on patients with functional dyspepsia whose main symptoms were postprandial fullness, upper abdominal bloating, and early satiation, and who were allowed to interrupt, resume, discontinue, or terminate the treatment depending on the improvement of the symptoms at visit to hospital every 4 weeks^{Note 8)}, the improvement rates of the subjects' impression were 48.9% (193/395) and 48.9% (69/141) at Week 4 and Week 24, respectively. The treatment was continued up to Week 24 without interruption in 22 out of 405 subjects, which demonstrates that long-term treatment with this product was required only in limited patients. The treatment was interrupted due to improvement of the symptoms in 75.1% (304/405), and 50.7% (154/304) of these subjects exhibited continuing improvement of the symptoms for 12 weeks and terminated the treatment.
Note 8) Patients aged 20 to 79 years who have presented with at least one of the three symptoms (postprandial fullness, upper abdominal bloating, and early satiation) according to the Rome III criteria for at least 6 months before informed consent, and the symptom(s) have persisted for at least 3 months before informed consent.
The incidence rate of adverse drug reactions was 11.5% (47/408). The major adverse drug reactions were constipation, diarrhea (2.2%, 9/408 each), and ALT increased (1.5%, 6/408). [See Important precautions under Precautions.]
Pharmacokinetics: Blood level: Single-dose administration: When one tablet of this product (100 mg as acotiamide hydrochloride hydrate) was administered to healthy adult males as a single oral dose in a fasted state, changes over time in the plasma unchanged drug concentration and pharmacokinetic parameters were as presented as follows. (See Figure 3 and Table 5.)

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Repeated-dose administration: When one tablet of this product (100 mg as acotiamide hydrochloride hydrate) was administered to healthy adult males as repeated oral doses three times daily before meals for nine days (single dose on Day 1, before every meal on Days 3-8, and single dose on Day 9), the plasma concentration reached almost a steady state after the third dose on Day 3. The pharmacokinetics were hardly changed by repeated-dose administration. (See Figure 4.)

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Absorption: Effect of food: When one tablet of this product (100 mg as acotiamide hydrochloride hydrate) was administered orally to healthy adult males in a fasted state, before or after meals, the C_max was the highest after preprandial administration and increased by 62.7% compared with that after fasted administration. The C_max after postprandial administration was 59.6% of that after preprandial administration. The AUC_last was the lowest after postprandial administration and decreased to 76.8% and 80.0% from that after fasted and preprandial administration, respectively. (See Figure 5.)

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Distribution: Plasma protein binding rate: The plasma protein binding rates determined by in vitro equilibrium dialysis were 84.21%-85.95% in human plasma and 82.64%-85.10% in human serum albumin showing comparable binding rates; therefore, the major binding protein was suggested to be albumin.
Metabolism: Metabolism: When [¹⁴C] acotiamide solution (600 mg/103 μCi) was administered orally to six healthy adult males in a fasted state, 60.0% of plasma radioactivity was observed in the unchanged drug. In addition, deisopropyl forms, unchanged glucuronate conjugates, and deisopropyl glucuronate conjugates were found in plasma (Data in non-Japanese subjects).
Metabolic enzymes: The findings of the in vitro metabolism assay in human CYP-expressed microsomes suggested that this product is metabolized by CYP2C8, CYP1A1, or CYP3A4 into deisopropyl forms. Also, the findings of the in vitro metabolism assay in human UGT-expressed microsomes suggested that this product is metabolized by UGT1A8 or UGT1A9 into unchanged glucuronate conjugates.
Excretion: When [¹⁴C] acotiamide solution (600 mg/103 μCi) was administered orally to six healthy adult males in a fasted state, the product was excreted in feces and urine as the total radioactivity in 92.7% and 5.3%, respectively, of the dose by 216 h post-dose (Data in non-Japanese subjects).
Toxicology: Preclinical Safety data: Safety Pharmacology: The in vitro studies of hERG channels have shown that acotiamide at 1×10^-4 mol/L significantly inhibited in HEK293 cells treated with 1×10^-7, 1×10^-6, 1×10^-5, and 1×10^-4 mol/L. In the rabbit ventricular myocytes, acotiamide inhibited I_Kr, with an IC₅₀ of 5.4×10^-5 mol/L. In the isolated guinea pig papillary muscle, acotiamide significantly prolonged the action potential duration (APD₅₀) at 1×10^-4 mol/L, but did not affect the other cardiac action potential parameters (resting membrane potential, action potential amplitude, maximum rate of rise).
In dogs, acotiamide did not affect the QT/QTc interval at 100 and 1000 mg/kg, but vomiting, decreased diastolic blood pressure and heart rate were observed at 100 mg/kg, and vomiting, salivation and shortened RR interval were observed at 1,000 mg/kg. In guinea pigs, acotiamide at 10 mg/kg significantly prolonged the epicardial monophasic action potential duration (MAPD₇₀ and MAPD₉₀), the QT, QTcB, and QTcF intervals, but there was no significant difference in the percent change from baseline of each MAPD and the QT interval. Acotiamide at 10 mg/kg significantly increased the mean, systolic, and diastolic blood pressures.
Toxicology: The approximate lethal dose (ALD) for acotiamide in dogs given single oral doses of 60, 200, 600 or 2,000 mg/kg was >2,000 mg/kg. In dogs, acotiamide showed the increased incidence and/or duration of miosis with increasing dose, vomiting or vomiting-like behavior at 600 mg/kg and above, and loose stool, decreased locomotor activity, and twitching at 2,000 mg/kg. The no observable adverse effect level (NOAEL) for acotiamide for repeated dose toxicity in dogs given oral doses of 100, 300 or 1,000 mg/kg for 4-week or oral doses of 30, 100 or 300 mg/kg for 3-month was 100 mg/kg. The NOAEL in male dogs and in female dogs given oral doses of 30, 100 or 300 mg/kg for 9-month were 30 mg/kg and 100 mg/kg respectively. Increased incidence of loose and/or liquid stool, vomiting and/or vomiting-like behavior, miosis, lacrimation, hyperemia of bulbar conjunctiva/upper sclera, and high levels of total cholesterol were observed at 300 mg/kg and above. Exposure of nictitating membrane, palpebral edema, tremor, decreased locomotor activity, abnormal gait, and high levels of phospholipids were observed at 1,000 mg/kg.
Genotoxicity: The bacterial reverse mutation test (Ames test) for acotiamide was negative, and acotiamide was considered to have no potential to induce gene mutations. The micronucleus test for acotiamide in rats also showed negative result, and acotiamide was considered to have no potential to induce micronuclei. In the chromosome aberration study in cultured mammalian cells, acotiamide was considered to have the potential to induce chromosome aberrations, although extremely weakly, at a high (4 mg/mL) and cytotoxic (cell viability ≤50%) concentration. However, the results of the additional studies (i.e., the in vitro chromosome aberration study in human peripheral blood lymphocytes and the in vivo/in vitro unscheduled DNA synthesis (UDS) test in rat hepatocytes) were negative. Acotiamide was determined to have no genotoxic potential in humans.
Carcinogenic Potential: The carcinogenicity studies of acotiamide in rats given the repeated oral doses of 200, 600, or 2,000 mg/kg for 4-week, 13-week, or 24-month, have showed no carcinogenic potential.
Reproduction and Development: In fertility and early embryonic development to implantation studies, acotiamide had no effects on histopathological examination of reproductive organs in rats at oral doses of 100, 300 or 1,000 mg/kg/day. In embryo-fetal development studies, acotiamide had no effects on the number of live fetuses, conceptus mortality, or the results of external, visceral, and skeletal examinations of live fetuses in rats or rabbits given oral doses of 100, 300 or 1,000 mg/kg/day. In the Pre- and postnatal development studies, including maternal function, acotiamide had no deaths, abortions, or total resorption of embryos throughout the gestation and lactation periods (F0) in rats at oral doses of 100, 300 or 1,000 mg/kg/day. Acotiamide had no effects on the general conditions, body weight, food intake, necropsy findings, organ weights, or delivery and lactating behaviour (F0) in rats given oral doses of 100, 300 or 1,000 mg/kg/day. Acotiamide had no effect for offspring (F1, F2).