Pharmacodynamics and pharmacokinetics
Itopride hydrochloride stimulates the digestive tract, as it is an antagonist of D2-dopamine receptors and inhibits the production of acetylcholinesterase . The substance inhibits the release of acetylcholine , preventing its destruction.
This drug also has an antiemetic effect, as it interacts with special receptors located in the trigger zone. The degree of suppression of vomiting depends on the dose taken; the substance eliminates vomiting caused by apomorphine .
Itopride stimulates the stomach, activating propulsive motility (inhibits the activity of acetylcholinesterase ). The effect of the drug is manifested in relation to the upper parts of the digestive tract, the movement of food through the esophagus and stomach is accelerated, and its emptying is accelerated and activated. The medicine does not affect the level of gastrin in the blood serum.
The product is absorbed quickly from the digestive tract. Bioavailability is about 60%. The maximum concentration is observed after 30-45 minutes (50 mg of the drug was taken). Repeated administration of 100-200 mg, several times a day for a week does not lead to the accumulation of the drug in the body, the pharmacokinetic parameters remain linear.
Itopride drugs are distributed throughout many tissues and organs, including the kidneys, stomach, small intestine, liver, and adrenal glands. The substance is found in lower concentrations in the spinal cord and brain, and in breast milk. Metabolism of the drug occurs in the liver under the influence of the enzyme flavin-dependent monooxygenase . The medicine is excreted through the kidneys, the half-life is 6 hours.
Functional dyspepsia (FD) is characterized by pain or discomfort in the epigastrium or discomfort, heartburn, feeling of fullness after eating and early satiety in the absence of other organic pathology that could explain these symptoms [1]. The prevalence of FD in the general population is 20-30% [2-4]. FD is not a life-threatening disease, so many patients do not begin treatment at an early stage of the disease. However, ignoring FD symptoms can negatively impact quality of life and become an important and costly health problem over the long term [5–7]. The issue of drug treatment for FD remains open. Acid-suppressing drugs (histamine H2 receptor antagonists and proton pump inhibitors (PPIs)) are included in the first-line treatment regimen, but in most cases relief occurs due to resolution of reflux symptoms and previously undiagnosed gastroesophageal reflux disease [1]. PPI therapy is effective for epigastric pain syndrome, but not for the so-called postprandial distress syndrome [1]. It has been established that one of the reasons for the symptom of fullness after eating is delayed gastric emptying [6]. Prokinetic agents such as cisapride, metoclopramide, and domperidone are believed to increase gastric emptying efficiency and have been reported to be effective in the treatment of FD [2].
Clinical studies assessing the effectiveness and safety of the gastrokinetic drug itopride were conducted in Europe [8, 9], Japan [10-13] and China [14]. There are very few clinical studies evaluating the effectiveness of itopride for the treatment of FD in Caucasians, and some studies have reported conflicting results [8, 9].
This study was conducted to assess the safety and effectiveness of itopride in patients in Russia to obtain local clinical data and experience supporting registration of the drug.
Materials and methods
A prospective, open-label, multicenter, outpatient, phase IV study was conducted using the placebo response obtained in previous studies as a control [8, 9]. An active control group was not included in the study. The study consisted of a screening period at week 1, an 8-week treatment period, and a 4-week post-treatment observation period. The structure of the study is presented in Fig. 1
.
Figure 1. Study design including screening and week 12 follow-up visit.
The study was conducted in accordance with the protocol, the principles of the Declaration of Helsinki, and the Good Clinical Practice guidelines of the International Conference on Harmonization of Technical Requirements for Registration of Medicinal Products for Human Use (ICH GCP). The study was carried out in accordance with the requirements for registration studies of the Ministry of Health of the Russian Federation. The clinical trial protocol, participant information, and informed consent were approved by the Independent Ethics Committee. The study was also approved by local regulatory authorities (Ministry of Health and Social Development of the Russian Federation). Before inclusion in the study, all patients signed informed consent. The study was conducted in 3 centers of two large cities of the Russian Federation: Moscow and St. Petersburg. Study population.
Inclusion criteria for the study were outpatient treatment, male or female gender, age over 18 years, presence of symptoms (pain or discomfort) in the upper abdomen for at least 12 weeks (not necessarily consecutive), satisfying the Rome II criteria [2] for the diagnosis of FD . Discomfort associated with FD was characterized by the following symptoms: epigastric pain, heartburn, belching, early satiety, feeling of fullness, bloating in the upper abdomen, nausea and vomiting. The study was designed before 2006 and therefore did not apply the Rome III criteria [13].
Exclusion criteria included any clinically significant changes on the electrocardiogram (ECG), symptoms indicating worsening of the condition (eg, hematemesis, jaundice, dysphagia, fever, sudden and unintentional weight loss >3.5 kg), history of gastrointestinal bleeding , mechanical obstruction or perforation of the intestine, any severe diseases of the liver, kidneys, heart, metabolic, hematological or malignant diseases, trimethylaminuria, hypokalemia, hypomagnesemia and psychiatric diseases. Breastfeeding mothers, pregnant women, and women of childbearing potential who were not using approved contraceptive methods were also excluded. Patients with intolerance to certain foods, hypersensitivity to the study drug, dependence on laxatives, those who had recently started or stopped smoking, or those suffering from alcoholism or drug addiction were not included. Patients were also excluded if they received eradication therapy for Helicobacter pylori
, antipsychotics or antidepressants during the last 3 months before enrollment, nonsteroidal anti-inflammatory drugs within 4 weeks before randomization, histamine H2 blockers or PPIs during the last 3 weeks before enrollment, or analgesics, parasympathomimetics or any antiemetics, drugs , prolonging the
QT
or
QTc
, antiarrhythmic drugs, and also if patients received other PD treatment.
Study treatment and intervention.
The study began with a screening period of 1 week.
All patients meeting the inclusion criteria and none of the exclusion criteria were prescribed itopride tablets 50 mg (Ganaton, Abbott) 3 times a day 30 minutes before meals for 8 weeks, after which treatment was stopped. 4 weeks after stopping treatment, the patient visited the doctor for follow-up (see Fig. 1)
.
Assessment of clinical outcomes.
Efficiency.
In accordance with generally accepted recommendations for clinical trials in functional pathology of the gastrointestinal tract (GIT) [15], the main outcome measure was the Global Patient Assessment (GPA) at week 8. Patients were asked to rate the effect of the drug on upper gastrointestinal symptoms during treatment by marking one of the following options: symptoms completely resolved, markedly improved, slightly improved, unchanged, or worsened. Clinically significant response to treatment was defined as patient ratings of “symptoms completely resolved” and “marked improvement.”
Additional efficacy indicators were: a) changes in the overall severity of FD from baseline to week 8 according to the Leeds Dyspepsia Questionnaire (LDQ) scale [16]; b) LDQ score at week 4 and at the follow-up visit (week 12); c) the number of patients who achieved a therapeutic effect in the form of improvement in one of the symptoms - pain or a feeling of fullness of the stomach - on the LDQ scale; d) the number of patients who achieved a treatment effect and who responded “symptoms completely resolved” and “marked improvement” according to GPA at weeks 4 and 12 (control visit).
The LDQ was used to assess additional performance indicators, i.e. presence and severity of dyspepsia. The patient answered questions personally at weeks 0, 4, 8, and 12 (control visit 4 weeks after completion of treatment).
Safety.
The main safety indicators were the following: incidence of adverse events (AEs), their severity, and association with the study drug. The safety of itopride was also assessed by indicators of vital body functions (blood pressure, pulse), by the results of laboratory tests (hematological, biochemical, including indicators of kidney and liver function, 12-lead ECG) and by the incidence of AEs. In addition, concomitant medications were taken into account.
Compliance with the protocol and “adherence to treatment.”
The physician could terminate any patient's participation in the study based on the results of the clinical evaluation or if the patient did not comply with the protocol. If a patient was withdrawn from the study early, this was noted in the journal indicating the reason for exclusion. If a patient was excluded due to an AE, the investigator continued to monitor the patient until clinical resolution of the event.
The number of tablets taken was indicated in the patient's registration card. Adherence to treatment was analyzed at weeks 4 and 8 by counting returned tablets. The criterion for “adherence to treatment” was taking 90% of the drug doses.
Statistical analysis.
Determining sample size.
The response rate for itopride has been previously estimated to be 60% and the response rate for historical placebo control to be 45% based on previous randomized placebo-controlled trials [8, 9]. In addition, it is taken into account that the number of patients who do not meet the inclusion and exclusion criteria at the screening stage will not exceed 30%, and the number of patients excluded from the study for any reason will also not exceed 30%. Based on these assumptions, a sample size of 100 patients was selected at a significance level of 5% (two-sided test) and power of 85%.
Statistical data processing.
Data obtained at weeks 0, 4, 8 and 12 (control visit) were used to assess the effectiveness and safety of itopride in patients with FD.
Safety was assessed in patients who received at least one dose of study drug and efficacy in those who completed at least one efficacy assessment after the baseline assessment at week 0.
For statistical assessment of the main effectiveness indicators, changes in the &khgr;2 criterion from baseline to week 8 were used. The test result is presented in the format: test statistic, degree of freedom (df) and p
. Additional performance measures were analyzed using Wilcoxon matched pairs test and Friedman ANOVA.
Key safety outcomes such as physical examination, vital signs, and laboratory data were analyzed using the Wilcoxon matched-pairs test. In addition, ECG results were analyzed using frequency tables. For any missing data, the Last observation carried forward (LOCF) analysis was used. Statistical analysis, tabulation, patient data listing, and figures were performed using SPSS version 16.0. Statistical significance was set at p
<0,05.
Data on AEs are summarized and presented in the form of system-organ classes and MedDRA preferred terms in accordance with the MedDRA coding dictionary version 13.0. Concomitant use of drugs and other medical products is coded using the WHO Drug Dictionary version 2010.
results
Distribution of patients.
Of the 100 patients examined, 96 (mean age 46.5 years, 40 men and 56 women) were included in the study.
For various reasons, 6 patients were excluded from the study (Fig. 2)
;
91 patients achieved the “primary endpoint” and 90 patients achieved the “secondary endpoints”, 1 completed the study early (see Fig. 2)
.
Figure 2. Distribution of patients during the study.
Data from all patients who met the primary endpoint were analyzed by treatment assignment in accordance with the overall sample analysis approach. "Adherence to treatment."
According to the records of used tablets, at week 4 all analyzed patients (
n
= 93) were “adherent to treatment”, as they took at least 90% of the drug doses. At week 8, 88 (96.7%) of 91 patients had taken at least 90% of drug doses.
Efficiency parameters.
In 78 patients (85.71%) according to GPA from 0 to 8 weeks, the answers “symptoms completely resolved” or “marked improvement” were obtained
(see table)
.
Comparison of this rate of achieving the therapeutic effect of itopride with the response rate in the historical placebo control group (45%) [9] using the &khgr;2 criterion showed statistically significant differences (&khgr;2=68.868; df=3; p
<0.0001) , presented in
Fig.
3 . Figure 3. Number of patients responding to itopride therapy as assessed by GPA (“symptoms resolved” and “significant improvement”) compared with placebo at week 8 [8].
Additional outcome measures, change in FD severity as measured by the LDQ, were examined using the Wilcoxon matched-pairs test. As shown in Fig. 4
, the overall severity of FD, according to the LDQ, at week 0 was 9.36 ± 4.56 points (hereinafter the mean value ± SD is presented).
Figure 4. Mean dyspepsia symptom scores based on the LDQ from weeks 0 to 12. n is the number of patients analyzed. * — p<0.0001. It decreased to 4.20±2.78 points ( p
<0.0001) at week 4 and to 2.09±1.98 points (
p
<0.0001) at week 8. It should be noted that the overall severity score remained approximately at the same level (2.01 ± 2.33 points) at the time of the follow-up visit 4 weeks after the end of treatment (week 12).
The rate of achieving a therapeutic effect in the form of improvement in one of the symptoms (pain or feeling of fullness in the stomach) compared to the initial state (0th week) was 76.34% at week 4 and 89.24% at week 8.
The number of patients who answered “symptoms completely resolved” and “marked improvement” according to GPA at weeks 4 and 12 (follow-up visit) was 53.76 and 82.22%, respectively, suggesting that the effect of treatment persisted for 4 weeks after discontinuation of itopride.
Safety assessment.
The main safety outcome was the incidence of AEs, their severity, and their relationship to the study drug. The safety analysis included AEs, medical examination findings, physical examination findings, laboratory findings, and ECG findings. The average duration of use of the study drug was 55 days. There were no deaths during the study.
A total of 6 AEs were recorded during the study, occurring in 3 (3.12%) patients included in the study. Moreover, 4 AEs occurred during treatment before the 8th week, and the rest were recorded during the follow-up period (from the 8th to the 12th week); 5 AEs were assessed as mild (vomiting, flu, ECG changes and 2 cases of increased creatinine kinase levels), while 1 AE was assessed as moderately severe (acute adnexitis). This adverse event occurred several days after enrollment and led to the patient's discontinuation from the study.
One mild AE (ECG changes) detected during the period after completion of the drug course was assessed as related to the study drug. In a 32-year-old woman with no clinically significant ECG abnormalities and no history of cardiovascular disease, an ECG at a follow-up visit at week 12 revealed asymptomatic atrial premature beats that spontaneously disappeared a few days later.
No changes in laboratory parameters (including liver and kidney function tests) were observed after completion of treatment at week 8 and at follow-up at week 12.
Discussion
Treatment of functional gastrointestinal disorders remains an area of active research. Symptoms can be caused by various motility disorders: slow gastric motor function is detected in 17-40%, and gastric dysrhythmia is detected in 40-55% of patients with FD [17, 18]. This explains the clinical effectiveness of the use of prokinetic drugs such as domperidone, cisapride or itopride in the treatment of FD. Three randomized, placebo-controlled clinical trials demonstrated the effectiveness of itopride in FD, but the results were inconsistent [8, 9].
A placebo-controlled phase II clinical trial revealed a significantly greater number of patients who achieved a therapeutic effect with itopride according to GPA compared with the placebo group, but in 2 subsequent phase III trials, no reduction in the severity of symptoms was detected with itopride treatment compared with placebo .
In the present study, we assessed the safety and effectiveness of itopride for the treatment of FD in patients in Russia, including in comparison with historical placebo control.
Itopride has a dual mechanism of action: it is a dopamine (D2) receptor antagonist and an acetylcholinesterase inhibitor. Both actions increase acetylcholine levels, which in turn increases gastrointestinal motility [19–21]. Itopride does not penetrate the blood-brain barrier, and therefore its use is not accompanied by the risk of extrapyramidal side effects [9]. Many drugs are metabolized by the cytochrome P (CYP) family of enzymes, and itopride is metabolized by the flavin-containing monooxygenase system. Therefore, when using itopride, metabolic competition and, as a result, drug interactions are less expected [22]. Itopride does not have tropism for cardiac 5-HT4 receptors, which causes side effects in the form of impaired cardiac function (prolongation of the QT
), characteristic of cisapride and other prokinetic drugs [22, 23].
We observed that itopride significantly improved symptoms in patients with FD. This study compared the rate of achieving a therapeutic effect after 8 weeks of treatment with PD itopride with previously obtained data for placebo, where the rate of achieving a therapeutic effect was 45%.
The response rate at the week 12 follow-up visit (82.22%) was also higher than the placebo response rate. This indicates that the benefits of itopride persist even after discontinuation of the drug. Previous studies using similar endpoints have found itopride to be safe and effective for 8 weeks in the treatment of FD. However, these studies did not include follow-up to assess the extent to which the effect was maintained after drug discontinuation [8, 9].
In our study, the overall severity of FD, as assessed by the LDQ, decreased from week 0 to weeks 4, 8, and 12. The same result was observed in a previous placebo-controlled study [8] - the itopride group showed a 50% greater improvement in FD symptom scores compared with the placebo response in historical controls.
It should be noted that the results of our study differ from those obtained in the study by N. Talley et al. [9]. Unlike these authors, we did not exclude patients who suffered from heartburn or who had H. pylori
, often associated with FD and often a predictor of response to pharmacological therapy [24]. In addition, the inclusion criteria for our study were not limited to an LDQ score greater than 9; this means that patients in the study population were not limited to those with high pain and fullness symptom scores, who tend to have high placebo response rates [24].
Although we found one mild AE considered to be related to the study drug, atrial premature contractions, it was asymptomatic and resolved without specific treatment within a few days.
The main limitations of the study were its non-comparative nature and the relatively small number of patients and centers. The study design was chosen based on the typical approach used for local clinical trials in Russia in order to support the registration of drugs launched on the market in other countries. Ganaton was registered in Russia in 2006.
Conclusion
Itopride demonstrated efficacy and good tolerability in the treatment of FD in patients in Russia. The effectiveness of itopride was maintained for 4 weeks after completion of treatment.
Acknowledgments
The study was developed and carried out with the support of Abbott Laboratories, Russia. We would like to thank Dr. Alexander Akimov, Abbott Clinical Project Manager, for assistance with statistical analysis, and Dr. Kirill Sokolov, Senior Medical Advisor, Abbott Laboratories, for assistance with translation and review of the manuscript.
Side effects
Itopride can cause:
- leukopenia , thrombocytopenia , gynecomastia , urticaria and anaphylactic reactions;
- hyperprolactinemia , nausea, excessive salivation, diarrhea , constipation;
- increased activity of liver enzymes, jaundice , hyperbilirubinemia ;
- tremors , headaches , dizziness .
Interaction
The medicine enhances gastrointestinal , affects the absorption time of other drugs, and most often accelerates it.
Particular care must be taken when combining the drug with long-acting, enteric-coated drugs with a low therapeutic index.
Combination use of the substance with anticholinergic drugs reduces the effectiveness of Itopride.
Is it possible to take Emanera and Itopride at the same time?
Such a combination is possible. Most often, Emanera is prescribed in the morning before meals along with Itopride and before going to bed.
Retch tab film 50mg 40 pcs
Pharmacological group:
Gastrointestinal motility stimulator - acetylcholine release stimulator.
Pharmacodynamics:
Strengthens the motility of the gastrointestinal tract (GIT) due to antagonism of D2-dopamine receptors and inhibition of acetylcholinesterase. Activates the release of acetylcholine and inhibits its destruction.
It has an antiemetic effect due to interaction with D2 receptors located in the trigger zone. Causes dose-dependent suppression of apomorphine-induced vomiting.
Activates propulsive gastric motility through antagonism of D2 receptors and dose-dependent inhibition of acetylcholinesterase activity.
The effect of the drug in patients with functional dyspepsia leads to a decrease in the severity of symptoms (general assessment by the patient, postprandial heaviness in the abdomen, early satiety).
The use of itopride in patients with diabetic gastroparesis helped to accelerate the evacuation of liquid and solid food from the stomach.
In patients with gastroesophageal reflux disease (GERD), itopride reduces the number of transient relaxations of the lower esophageal sphincter and reduces the length of time with high esophageal acidity (pH).
It has a specific effect on the smooth muscles of the gastrointestinal tract, accelerates transit through the stomach and improves its emptying. Does not affect serum gastrin concentrations.
Pharmacokinetics:
Suction.
Quickly and almost completely absorbed into the gastrointestinal tract. Its relative bioavailability is 60%, which is associated with first-pass metabolism through the liver.
The maximum concentration in plasma (Cmax) is 0.28 mcg/ml, after taking 50 mg of the drug, achieved after 0.5-0.75 hours. When the drug is taken orally at a dose of 50-200 mg three times a day for 7 days, pharmacokinetics has a linear character, cumulation is minimal.
Distribution.
Binds to plasma proteins by 96%, mainly to albumin. Binding to alpha1-acid glycoprotein is less than 15%.
Actively distributed in tissues (volume of distribution 6.1 l/kg) and found in high concentrations in the kidneys, small intestine, liver, adrenal glands and stomach. In therapeutic doses, it slightly penetrates into the brain and spinal cord and into breast milk.
Metabolism.
Metabolized in the liver. 3 metabolites have been identified, one of which exhibits minor activity that has no pharmacological significance (approximately 2-3% of that of itopride). The primary metabolite in humans is N-oxide, which is formed as a result of oxidation of the quaternary amino-N-dimethyl group.
Metabolized by flavin-dependent monooxygenase (FMO3). The number and effectiveness of human isoenzymes may vary due to genetic polymorphisms, which in rare cases lead to the development of an autosomal recessive condition known as trimethylaminuria (fishy odor syndrome).
In patients with trimethylaminuria, the half-life of the drug increases.
The drug does not have an inhibitory or inducing effect on CYP2C19 and CYP2E1. The use of itopride does not affect the activity of uridine diphosphate glucuronyl transferase.
Excretion.
Itopride and its metabolites are excreted by the kidneys. Renal excretion of itopride and its N-oxide after a single oral dose of the drug in therapeutic doses in healthy people was 3.7 and 75.4%, respectively.
The half-life of the drug (T1/2) is 6 hours.
Preparations containing (Itopride analogues)
Level 4 ATX code matches:
Passazhix
Motinorm
Domrid
Motilium
Itomed
Metoclopramide
Domperidone
Motilak
Ganaton
Cerucal
Structural analogues: Ganaton , Itopra , Itomed .
Reviews
Some reviews about taking Itopride drugs:
- “... I began to experience pain in the right hypochondrium, as if I had pancreatitis. I self-medicated for a week, took handfuls of pills, nothing helped. Then, when I went to the doctor, I was prescribed this remedy. It felt better after the first dose”;
- “... A year after giving birth, my stomach began to hurt. The doctor diagnosed a hiatal hernia. I prescribed this medicine, took it for a month and everything got better. Now sometimes I take it before a feast or a visit, so that there is no heaviness in the stomach later”;
- “... This medicine did not suit me. After the first pill, it covered everything, I began to feel sick and had a headache, my allergies were severe. They called an ambulance, it’s good that everything worked out.”
Ganaton tablets 50 mg 40 pcs. in Moscow
Film-coated tablets
white, round, with a mark on one side and an engraving “HC 803” on the other.
Suction.
Itopride hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. Its relative bioavailability is 60%, which is associated with first-pass metabolism through the liver. Food has no effect on bioavailability.
After taking 50 mg of itopride hydrochloride orally, Cmax is reached after 0.5–0.75 hours and is 0.28 mcg/ml. When the drug was repeated at a dose of 50–200 mg 3 times a day for 7 days, the pharmacokinetics of the drug and its metabolites were linear, and accumulation was minimal.
Distribution.
Binds to plasma proteins (mainly albumin) by 96%. Binding to α1-acid glycoprotein accounts for less than 15% of total binding.
Actively distributed in tissues (Vd is 6.1 l/kg) and is found in high concentrations in the kidneys, small intestine, liver, adrenal glands and stomach. Penetrates the brain and spinal cord in minimal quantities. Passes into breast milk.
Metabolism.
Itopride undergoes active biotransformation in the liver. 3 metabolites have been identified, only one of which exhibits small activity that has no pharmacological significance (approximately 2–3% of that of itopride). The primary metabolite is N-oxide, which is formed as a result of oxidation of the quaternary amino-N-dimethyl group.
Itopride is metabolized by flavin-dependent monooxygenase (FMO3). The amount and effectiveness of FMO3 isoenzymes in humans may vary depending on genetic polymorphisms, which in rare cases lead to the development of an autosomal recessive condition known as trimethylaminuria (fishy odor syndrome). In patients with trimethylaminuria, T1/2 of itopride increases.
Based on in vivo
, itopride does not have an inhibitory or inducing effect on CYP2C19 and CYP2E1. Itopride therapy does not affect CYP or uridine diphosphate glucuronyl transferase activity.
Excretion.
Itopride hydrochloride and its metabolites are excreted mainly in the urine. Renal excretion of itopride and its N-oxide after a single oral dose of the drug in therapeutic doses in healthy people was 3.7 and 75.4%, respectively.
Terminal T1/2 of itopride hydrochloride is about 6 hours.
Mechanism of action.
Itopride hydrochloride enhances gastric motility by antagonizing D2-dopamine receptors and inhibiting acetylcholinesterase. Itopride activates the release of acetylcholine and inhibits its destruction.
Itopride hydrochloride also provides an antiemetic effect due to interaction with D2 receptors located in the trigger zone. Itopride causes dose-dependent suppression of apomorphine-induced vomiting.
Itopride hydrochloride activates propulsive gastric motility through antagonism of D2 receptors and dose-dependent inhibition of acetylcholinesterase activity.
Itopride hydrochloride has a specific effect on the upper gastrointestinal tract, accelerates gastric transit and improves gastric emptying. Itopride hydrochloride does not affect serum gastrin levels.
