Trimetazidine Modified Release Research Articles

Anti-Anginal Effectiveness and Tolerability of Trimetazidine Modified Release 80Mg Once Daily in Stable Angina Patients in Real-World Practice.

IntroductionTrimetazidine (TMZ) was shown to reduce angina symptoms and increase the exercise capacity in stable angina (SA) patients. A new formulation allowing a once-daily (od) dosage could improve patients’ satisfaction and adherence.MethodsODA was a 3-month, observational, multicenter, prospective Russian study in SA patients with persistent symptoms despite therapy. Angina attack frequency, short-acting nitrate (SAN) consumption, adherence to antianginal medications, and overall efficacy and tolerability of TMZ 80 mg od were assessed in a real-world setting.ResultsA total of 3066 patients were included (mean age 62.8, 48% male). After 3 months, TMZ 80 mg od treatment led to a significant (p < 0.001) decrease in angina attack frequency (from 4.7 ± 3.5 to 0.9 ± 1.3/week) and SAN use (from 4.5 ± 3.9 to 0.7 ± 1.3/week). Overall tolerability and effectiveness were rated as “very good” by the majority of physicians. Medication adherence improved significantly, with good adherence reported by 56% of patients (vs. 24% at baseline, p < 0.0001) and non-adherence by 3% (vs. 36% at baseline, p < 0.0001) at month 3. Patient satisfaction with TMZ od was 9.5 [on a scale of 1 to 10 (very satisfied)]. Patients reported improved physical activity: more patients reported no limitations (15% vs. 1% at baseline p < 0.01), slight limitation (46% vs. 5% at baseline, p < 0.001) or moderate limitation (30% vs. 23%, p < 0.01) and fewer patients reported substantial limitation (8% vs. 52% at baseline, p < 0.001) or very marked reduction (1% vs. 19% at baseline, p < 0.01) at month 3.ConclusionIn this prospective, observational study, TMZ 80 mg od effectively reduced angina attacks and SAN consumption, improved physical activity and adherence and was well tolerated in chronic SA patients.Trial RegistrationISRCTN registry Identifier, ISRCTN97780949.FundingServier.Plain Language SummaryPlain language summary available for this article.

Clinical Acceptability Of Trimetazidine Modified-Release 80mg Once Daily Versus Trimetazidine Modified-Release 35mg Twice Daily In Stable Angina Pectoris.

IntroductionTrimetazidine (TMZ) is an anti-ischemic metabolic agent that has been shown to be efficacious in angina treatment, both in monotherapy and in combination. A new formulation of TMZ modified-release (MR) 80 mg was developed, which is to be taken once daily (od), instead of twice daily (bid) for the currently available TMZ MR 35 mg, with the aim of simplifying the medication regimen.MethodsThe present study was an international, multicenter, randomized, double-blind, parallel-group phase III study with a 12-week treatment period. The safety of TMZ MR 80 mg once daily was assessed compared to TMZ MR 35 mg twice daily, in patients previously treated successfully by the latter. Emergent adverse events (EAEs), biological parameters, vital signs, 12-lead resting ECG (electrocardiogram) and Canadian Cardiovascular Society (CCS) classification were recorded.ResultsOne-hundred and sixty-five patients previously diagnosed with stable angina pectoris on treatment were randomized to receive either TMZ MR 80 mg od or TMZ MR 35 mg bid. In the TMZ MR 80 mg group, fewer patients had ≥ 1 EAE (17.1 vs. 22.9% in the TMZ MR 35 mg group). Serious EAEs were reported by three patients in each group. No EAE required dose modification, withdrawal, or temporary interruption of study treatments. Vital signs, 12-lead ECG, and laboratory parameters did not change. No worsening in CCS classes was observed with either treatment.ConclusionsTMZ MR 80 mg od and TMZ MR 35 mg bid have similar safety profiles. This new once-daily formulation could improve patient compliance with therapy, thereby enhancing clinical benefit.Trial RegistrationISRCTN registry, ISRCTN 84362208.FundingInstitut de Recherches Internationales Servier and Servier, Moscow, Russian Federation.Plain Language SummaryPlain language summary available for this article.Electronic supplementary materialThe online version of this article (10.1007/s40119-018-0110-5) contains supplementary material, which is available to authorized users.

Bioequivalence of Trimetazidine Modified Release Tablet Formulations Assessed in Indonesian Subjects

This study was conducted in order to compare the bioavailability of two modified release tablets containing 35 mg of trimetazidine. Twenty-four subjects were enrolled in a single center, randomized, single dose, open label, two-way crossover study with a one-week washout period. Plasma samples were collected up 48 hours following drug administration and trimetazidine was determined by liquid chromatography-tandem mass spectrometry (LC- MS/MS) method with turboionspray mode. Pharmacokinetic parameters used for bioequivalence assessment were AUC 0-t , AUC 0- ∞ and C max . The 90% confidence intervals obtained by analysis of variance for AUC 0-t , AUC 0- ∞ and C max were 94.89-105.15%, 94.85-105.23%, 93.31-107.36%, respectively. These results were all within the range of 80.00-125.00%. Bioequivalence between formulations was concluded both in terms of rate and extent of absorption.

Food Effect on Bioavailability of Modified‐Release Trimetazidine Tablets

This study aimed to investigate a food effect on the bio-availability of modified-release (MR) trimetazidine tablets in 36 healthy volunteers. Trimetazidine, an anti-ischemic drug, protects the myocardial cell from the harmful effects of ischemia. The authors investigated the effect of being under a fasting or fed state at the time of drug intake on the bioavailability of trimetazidine 35-mg MR tablets in a randomized, open-label, crossover, 2-arm, 4-period, 2-sequence bioequivalence study design with a 14-day washout period. Plasma concentration of trimetazidine was assayed in timed samples with a validated high- performance liquid chromatography/mass selective detector that had a lower limit of quantification of 2.5 ng/mL. Test and reference formulations gave a mean trimetazidine C(max) of 63.26 ng/mL and 69.18 ng/mL for the fasting state and 64.19 ng/mL and 63.11 ng/mL for the fed state, respectively. The AUC(0-tlast) mean of trimetazidine was 726.31 ng·h/mL and 733.01 ng·h/mL for the fasting state and 706.40 ng·h/mL and 691.40 ng·h/mL for the fed state for test/reference formulations. There were no significant differences in pharmacokinetic parameters between the 2 formulations and the fasting/fed states. The authors showed that there is no food effect and no need for a 4-period study to evaluate the bioequivalence of trimetazidine MR tablets.

Bioequivalence Study of Two Formulations of 35mg Trimetazidine Modified Release Tablets in Healthy Thai Volunteers Under Fasting and Fed Conditions

Background: The generic product of trimetazidine, an anti-anginal agent, is currently available in Thailand. Bioequivalence study is used to compare rate and extent of absorption between generic and innovator’s products. Objective: To determine the bioavailability of two modified release tablets of 35mg trimetazidine dihydrochloride (Matenol ® MR; generic product and Vastarel ® MR; innovator’s product) Materials and methods: The study was conducted according to a single-dose, two-treatment, two-period, two- sequence randomized crossover design under fasting and fed conditions with a minimum of 7 days washout period. Twenty-four healthy Thai male and female volunteers were enrolled; however, only twenty-two subjects in the fasting group and twenty-three subjects in the fed group were completed the studies. For both conditions, each volunteer received a 35mg trimetazidine modified release tablet of both formulations. Every volunteers were obtained blood samples 16 times over a period of 24 hours after each oral administration.The trimetazidine plasma concentrations were quantified using a validated method employing liquid chromatography with tandem mass spectrometry with the lower limit of quantification of 0.25 ng/mL. All of the pharmacokinetic parameters were investigated using non- compartmental analysis model. Results: The 90% confidence interval of the geometric mean ratio of C max , AUC 0-t and AUC 0-∞ were within the equivalence criteria (80.00-125.00%) which were 105.53% (95.71%-116.36%), 104.28% (96.24%-112.98%, and 105.26% (96.61%-114.67%) under fasting condition and 110.21% (102.72%-118.25%), 101.95% (94.33%- 119.19%), and 99.7% (91.18%-109.02%) under fed condition, respectively. No statistical differences of median T max ( p >0.05) between two formulations in both conditions were observed. Furthermore, both preparations were well tolerated and had a few non-serious adverse events including nausea, dizziness, drowsiness and headache. Conclusion: These two trimetazidine products have comparable bioavailability.

Trimetazidine MR in Patients with Stable Angina in Bangladesh

The TRIUMPH– BANGLA (TRImetazidine MR in patients with stable angina: Unique Metabolic APproacH in BANGLAdesh) study was developed to provide information on the effect of trimetazidine modified release (MR) in patients with stable effort angina in Bangladesh. This medium term open-label, uncontrolled study was conducted in 88 patients with stable angina. Patients were treated with trimetazidine MR (35 mg tablet, twice a day) for 12 weeks in addition to their existing treatments. Overall 88 patients with stable angina (78 male and 10 female) aged 49.7 ± 7.5 years had completed the study. During the 12-week treatment period the number of angina attacks per week decreased significantly from 7.3 ± 6.6 to 2.1 ± 4.8 (p &lt; 0.0001). Concurrently the number of nitroglycerine use per week also decreased significantly from 4.1 ± 4.5 to 0.9 ± 1.5 (p &lt; 0 .0001).Patients’ quality of life, assessed on the Seattle Angina Questionnaire scores showed significant improvement (p &lt; 0.0001) from before treatment to after treatment for all five items evaluated - physical limitation from 57.7 ± 12.4 to 66.8 ± 10, angina stability from 24.7 ± 20.6 to 59.6 ± 15.2, angina frequency from 41.2 ± 21.8 to 63.4 ± 15.7, treatment satisfaction from 44.5 ± 21.8 to 57.9 ± 18.8 and disease perception from 50.7 ± 16.1 to 64.3 ± 14.9. None of the patients reported any adverse effect during the treatment period. The results of this study suggest an improvement in clinical efficacy and quality of life with good tolerance of trimetazidine MR at a dose of 35mg twice a day for 12 weeks in patients with stable angina in Bangladesh.University Heart Journal Vol.4(1) January 2008

Treatment of Stable Angina Pectoris with Trimetazidine Modified Release in Indian Primary-Care Practice

In primary-care practice, trimetazidine is frequently used in combination with other antianginal drugs to enhance antianginal efficacy because of its metabolic mode of action. This study investigates whether a new twice-daily trimetazidine modified release formulation with improved pharmacokinetic properties is more effective and acceptable than the older thrice-daily immediate-release formulation. In a multicenter prospective study, patients with uncontrolled stable angina pectoris receiving combination antianginal treatment that included the thrice-daily trimetazidine were identified. The immediate-release trimetazidine formulation was substituted with twice-daily trimetazidine modified release (Flavedon) MR), with no other changes in the treatment regimen. Follow-up was for 3 months. The primary outcomes were entirely clinical: frequency of anginal attacks and nitroglycerin (glyceryl trinitrate) consumption. In 279 patients, substitution of thrice-daily trimetazidine with twice-daily trimetazidine modified release reduced mean frequency of angina by four attacks per week (95% CI 3.1, 4.9; p < 0.01) and nitroglycerin consumption by 3.6 tablets per week (95% CI 2.9, 4.3; p < 0.01). The magnitude of these benefits was directly proportional to the number of antianginal drugs used in combination with trimetazidine. There were no withdrawals due to adverse effects, and daily compliance was 98%. The twice-daily trimetazidine modified release is more effective and acceptable than the thrice-daily formulation for the combination treatment of stable angina in primary-care practice.

Trimetazidine Modified Release in???the???Treatment of Stable Angina

To assess the clinical efficacy, safety and effects on quality of life of trimetazidine modified release (MR) in patients with stable angina. This large, open-label, uncontrolled study was conducted in 906 patients with stable angina in the Russian Federation. Patients were treated for 8 weeks with trimetazidine MR (35mg tablet, twice a day) in addition to their conventional therapy. Overall 846 patients (516 men and 330 women) aged 58.7 ±9 years completed the study. During the 8-week treatment period the number of angina attacks per week decreased continuously and significantly from 11.2 ±0.4 to 3.6 ±0.2 (p < 0.0001). Concurrently, the number of short-acting nitrate tablets taken per week decreased from 11.9 ±0.8 to 3.4 ±0.2 (p < 0.0001). Patients’ quality of life, assessed on the Seattle Angina Questionnaire, showed a significant improvement (p < 0.0001) for all five items evaluated: physical limitation increased from 50.7 ±0.7 to 61.0 ±0.6, angina stability improved from 57.6 ±0.9 to 92.5 ±0.7, angina frequency extended from 33.3 ±0.7 to 55.6 ±0.8, treatment satisfaction increased from 62.3 ±0.7 to 77.4 ±0.5, and disease perception improved from 36.7 ±0.6 to 55.5 ±0.7. Adverse events were reported in 2.4% of patients (22/906) during the 8 weeks of treatment. No serious adverse events were reported. The results of this study suggest an improvement in clinical efficacy and in quality of life and a good tolerance of trimetazidine MR administered at a dose of 35mg twice a day for 8 weeks in patients with stable angina.

Trimetazidine: a metabolic agent for the treatment of stable angina

It has been recently demonstrated that trimetazidine, known for years to be an effective antianginal agent, shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. By decreasing fatty acid oxidation, trimetazidine stimulates glucose utilization, restoring coupling between glycolysis and carbohydrate oxidation and leading to adenosine triphosphate production with lesser oxygen consumption. The antianginal properties of this agent are independent of haemodynamic changes, and dramatically improve recovery of mechanical function after ischaemia. Several studies have tested the efficacy of trimetazidine and have demonstrated this agent to be at least as effective as and better tolerated than haemodynamic agents. In stable effort angina, trimetazidine improves exercise tolerance and elevates the ischaemic threshold to an extent comparable with beta-blockers and calcium channel blockers. The combination of trimetazidine and a beta-blocker appears more effective than the combination of nitrates and a beta-blocker, and the addition of trimetazidine improves symptoms in patients resistant to diltiazem. The cardioprotective effects of trimetazidine have been recently confirmed in human ischaemia-reperfusion, including patients undergoing percutaneous coronary artery revascularization and bypass surgery with cardioplegic arrest. A new modified-release (MR) formulation of trimetazidine will shortly be introduced. A twice-daily regimen of these new MR tablets has been shown to be bioequivalent to the thrice-daily regimen of the previous formulation, and has been clinically tested in patients with stable angina pectoris resistant to beta-blockers. In a multicentre, international, double-blind, randomized, placebo-controlled study, the addition of trimetazidine MR tablets twice daily to atenolol 50 mg significantly prolonged the time to 1 mm ST depression and the time to onset of angina, with a favourable safety profile. The clinical safety of this new formulation has been confirmed in a double-blind, placebo-controlled study enrolling 234 elderly patients treated for 1 year. Safety and efficacy of trimetazidine MR promise to expand the role of metabolic agents for the treatment of ischaemic heart disease.