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Pharmacology: Pharmacodynamics: Itopride hydrochloride is an orally active gastroprokinetic agent. Itopride hydrochloride tablets contain 50 mg of itopride hydrochloride. The tablet has been formulated to provide immediate release. It is chemically designated as N-[4-[2-Dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride. Itopride hydrochloride is a substituted benzamide. It has an empirical formula of C20H26N2O4·HCl, molecular weight of 394.89 g/mol.
Mechanism of Action: Itopride has dual mechanism of action: dopamine D2 receptor antagonism and acetylcholinesterase inhibition. The effect of itopride is an increase in acetylcholine concentration, which promotes gastric motility, increases the lower oesophageal sphincter (LOS) pressure, accelerates gastric emptying and improves gastroduodenal coordination.
Itopride hydrochloride also has antiemetic action through interaction with D2 receptors located in the chemoreceptor trigger zone. This was demonstrated by dose dependent inhibition of apomorphineinduced vomiting in dogs.
In conscious dogs, itopride hydrochloride activates propulsive gastric motility through dopamine D2 receptor antagonistic actions and dose-dependent inhibition of acetylcholinesterase.
Itopride hydrochloride has been shown to accelerate gastric emptying in humans, dogs and rats.
In single-dose studies in dogs, itopride hydrochloride was shown to promote gastric emptying.
The action of itopride hydrochloride is highly specific for the upper gastrointestinal tract.
Itopride hydrochloride does not affect serum gastrin levels.
For functional dyspepsia (FD), the results of 2 placebo-controlled studies revealed statistically significant benefit or clear tendencies for the measured endpoints (Holtmann, 2003 and Yun, 2001). In Holtmann 2003, the symptom severity Leads dyspepsia questionnaire (LDQ) score of the difference between the placebo group and the pooled results of the itopride dose groups (50 mg, 100 mg and 200 mg tid) revealed superiority of itopride (P<0.05). Although the test for a dose response was not statistically significant (P=0.06) and the difference between placebo and itopride in the 50 mg tid dose revealed P=0.07, the other two doses were statistically significant (P=0.05). After 8 weeks, overall 41% of the patients receiving placebo were symptom-free or had marked improvement of their motility disorder compared to 57%, 59%, and 64% receiving itopride of 50, 100, or 200 mg tid, respectively (P<0.05 for all comparisons). The analysis of the combined endpoint of pain and fullness showed that itopride yielded a greater rate of response than placebo (73% vs. 63%, P<0.05). In Yun 2001, the baseline comparison of the symptom scores for motility disorder measured after 2 weeks: itopride (50 mg tid) 89.1%; placebo: 62.5% demonstrated that itopride was better than placebo for subject's global satisfactory evaluation and investigator's global evaluation, with statistical significance (P<0.05). It showed that itopride was effective in chronic gastritis with dyspepsia.
Overall, the study results of 19 efficacy studies in the category FD showed a positive effect of itopride and patients reported to benefit from itopride treatment. A controlled study of itopride versus mosapride (Amarapurkar 2004), showed a reduction of FD symptoms with both itopride and mosapride treatment and a higher reduction of the severity of symptoms in the itopride group. Statistically significant higher moderate to complete symptom relief was demonstrated with itopride versus metoclopramide (Kamath 1999). In Sawant 1999, patient symptom relief was better for itopride as compared with domperidone.
The results of a meta-analysis of 9 randomized controlled trials enrolling 2,620 FD cases were published by Huang et al. 2012. Compared with control groups (placebo, domperidone, mosapride), itopride had superior relative risk values for global patient assessment, postprandial fullness and early satiety. Itopride improved the LDQ scores more significantly than placebo. The meta-analysis from Wu et al. 2010 of 18 randomized controlled trials in 2,420 subjects showed that the relief rate of anorexia and early satiety in itopride group were statistically superior compared with domperidone.
Studies in diabetic gastroparesis showed that itopride tends to accelerate gastric emptying of liquids and solids in longstanding diabetes (Stevens, 2008). In non-insulin dependent diabetes mellitus patients a positive effect on diabetic gastroparesis (using acetaminophen and radiopaque markers) was found after 2 weeks of itopride (150 mg/day) treatment (Noritake Masayuki, 1997). Alpha-lipoic acid and itopride combination therapy can further improve symptoms of gastroparesis, increase gastric emptying, and decrease the levels of motilin and gastrin compared with treatment with itopride alone (Ma, 2015a). Combination treatment of itopride showed significant improvement in severity as well as the frequency of all the symptom parameters of the disease (Venkatesh, 2008).
Effectiveness of itopride in gastro-esophageal reflux disease (GERD) can in part be explained due to it inhibiting transient lower esophageal sphincter relaxations. (Scarpellini 2011) as well as significantly reducing the % time pH <4. The study results in GERD demonstrated that adding itopride to proton pump inhibitors (lansoprazole or pantoprazole) in the treatment of laryngopharyngeal reflux improves symptoms scores (Chun, 2013; Ezzat, 2011) shortens the need for oral medication, and reduces the rates of recurrence of symptoms after discontinuation of treatment (Ezzat, 2011). Itopride was more effective than domperidone in combination with omeprazole (a proton punp inhibitor) in the treatment of GERD in patients with diabetes mellitus (Fedorchenko, 2013) and also in an uncontrolled study symptoms scores improved in patients with GERD after itopride treatment (Choi, 2003).
Clinical Studies: The activity of itopride hydrochloride has been evaluated in two pivotal studies; a dose finding study and a comparative study.
Dose-Finding Study of Gastroprokinetic Agent, HSR-803, on Gastrointestinal Complaints - Late Phase II Study: A double blind comparative study evaluated 204 patients diagnosed with functional, non-ulcer dyspepsia (chronic gastritis), acute gastric mucosal lesions (AGML), gastric polyps with complaints of upper abdominal digestive symptoms such as upper abdominal fullness, heaviness of the stomach, epigastric pain, nausea, vomiting, heartburn, loss of appetite, discomfort, etc. The purpose of this study was to determine the optimal dosage of this drug. Using 3 treatment groups with a daily dosage level of 75 mg, 150 mg, or 300 mg, respectively, 188 cases were evaluated for drug efficacy.
The Final Global Improvement Ratings showed that the degree of improvement was 'moderate improvement' or better in 53.3% in the 75 mg group, 73.7% in the 150 mg group, and 66.2% in the 300 mg group, and a trend (p-value=0.065) was observed between the 3 groups using the chi-square test for differences in scores of 'moderate improvement' or better, with the 150 mg group showing a higher degree of improvement than the 75 mg group by Tukey-type multiple comparison (p-value=0.036).
When analyzed by symptom, the degree of improvement ('moderate improvement' or better) was higher at 2 weeks administration or at discontinuation compared to at 1 week administration for all symptoms, and with the exception of 'heartburn' which showed a low incidence, the 150 mg group showed the highest degree of improvement for every symptom.
The Usefulness Rating was 'useful' or better, in 53.3% in the 75 mg group, 71.9% in the 150 mg group, and 69.0% in the 300 mg group.
From the previously mentioned results, it was concluded that the optimal dosage of this drug is a daily dose of 150 mg.
Clinical Evaluation of Itopride Hydrochloride for Gastrointestinal Symptoms Associated with Chronic Gastritis Multicenter Double Blind Comparative Study Using Cisapride as a Control Drug: A multi-center, double-blind clinical trial, compared itopride hydrochloride with cisapride in 251 patients for upper abdominal digestive symptoms associated with functional, non-ulcer dyspepsia (chronic gastritis). The purpose of this study was to evaluate the efficacy, safety, and usefulness of itopride hydrochloride. Patients received either cisapride 2.5 mg t.i.d. or itopride hydrochloride 50 mg t.i.d. for a period of two weeks.
The cases subjected to efficacy evaluation consisted of 111 cases in group H (itopride hydrochloride) and 114 cases in group C (cisapride), for a total of 225 cases.
The Final Global Improvement Ratings showed that the improvement rate was 'moderate improvement' or better, in 79.3% in group H, 71.9% in group C, and there were no significant differences observed between the 2 groups.
When analyzed by symptom, the improvement rate scored as 'moderate' or better was 64.8 to 78.6% in group H and 57.8 to 81.3% in group C, and the disappearance rate for each symptom (within 14 days) was 58.0 to 92.9% in group H and 63.9% to 86.7% in group C. There were no significant differences observed between the 2 groups. However, for 'vomiting', group H showed a tendency to be superior to group C (p value=0.052) in the Global Improvement Rating at 1 week administration.
The usefulness rating was 'useful' or better, in 74.6% in group H and 69.6% in group C, with no significant differences observed between the 2 groups.
From the previously mentioned results, it was concluded that itopride hydrochloride is a clinically useful drug for the treatment of upper abdominal digestive symptoms associated with chronic gastritis.
Pharmacokinetics: Absorption: Itopride hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. Relative bioavailability is calculated to be 60% due to liver first pass metabolism. There is no effect of food on bioavailability. Peak plasma levels (Cmax 0.28 g/mL) are reached after 0.5 to 0.75 hours after 50 mg of itopride hydrochloride.
Following multiple oral doses ranging from 50 mg to 200 mg tid, itopride hydrochloride and its metabolites showed linear pharmacokinetics over a treatment period of seven days, with minimal accumulation.
Distribution: Approximately 96% of itopride hydrochloride is bound to plasma proteins. Albumin accounts for most of the binding. Alpha-1-acid-glycoprotein accounts for less than 15% of binding.
In rats, itopride is distributed extensively (Vdβ=6.1 L/kg) with high concentrations in the kidneys, small intestines, liver, adrenal glands, and stomach. Protein binding in the rat was lower than that seen in humans (78 vs 96%). The transfer into the central nervous system, including brain and spinal cord, was minimal. Itopride distributes into the breast milk of rats.
Metabolism: Itopride undergoes extensive hepatic metabolism in humans. Three (3) metabolites have been identified, of which only one exerts minor activity without pharmacological relevance (approximately 2-3% of that of itopride). The primary metabolite in humans is the N-oxide, generated by oxidation of the tertiary amine N-dimethyl group.
Itopride is metabolized by a flavin-dependent monooxygenase (FMO3). The abundance and efficiency of the human FMO-isozymes can be subject to genetic polymorphisms, which can lead to a rare autosomal recessive condition known as trimethylaminuria (fish odor syndrome).
Pharmacokinetics may differ between trimethylaminuria (TMAU) patients and non-trimethylaminuria (non-TMAU).
In vivo pharmacokinetic studies on CYP-mediated reactions revealed that itopride showed neither inhibitory nor inductor effect on CYP2C19 and CYP2E1. CYP content and uridine diphosphate glucuronosyl transferase activity were not altered with the administration of itopride.
Excretion: Itopride hydrochloride and its metabolites are primarily excreted in the urine. The urinary excretions of itopride and its N-oxide were 3.7% and 75.4%, respectively, in healthy subjects after oral administration of a single therapeutic dose (50 mg).
The terminal phase half-life of itopride hydrochloride was approximately six (6) hours.
Toxicology: Pre-Clinical Safety Data: Pre-clinical effects were observed only at dosages in excess of human dose indicating little relevance to human use. Moreover, humans are less susceptible to the hormonal effects observed in the animal models. High dosages (30 mg/kg/day) of itopride hydrochloride produced reversible mammary hyperplasia in rats, secondary to hyperprolactinemia, albeit not in dogs (to 100 mg/kg/day) or primates (to 300 mg/kg/day). A 3-month oral toxicity study in dogs, prostatic atrophy was observed at 30 mg/kg/day of itopride, albeit not after 6 months treatment with higher (100 mg/kg/day) dosages nor in rats or monkeys at even higher (300 mg/kg/day) dosages.
Long-term animal studies of itopride hydrochloride have not been conducted to evaluate carcinogenic potential.
No clastogenic or mutagenic effects of itopride hydrochloride were observed in a battery of in vitro and in vivo assays.
In a rat fertility study, prolonged estrous cycle was seen in female animals receiving ≥30 mg itopride/kg/day, secondary to hyperprolactinemia. In addition, a prolonged precoital interval was also seen at 300 mg/kg/day. However, the plasma concentrations of itopride in pregnant rats treated orally at 300 mg/kg were about 100-fold higher than the itopride concentrations observed in human serum after clinical administration (50 mg). There was no adverse effect on copulation or fertility. No teratogenic effect was observed in preclinical studies in rats and rabbits, at maternal doses of up to 300 mg/kg.
