Vastarel MR Mechanism of Action

Pharmacotherapeutic Group: Other Cardiovascular Antianginal Drug. ATC Code: C01EB15.
Pharmacology: Pharmacodynamics: Mechanism of Action: By preserving energy metabolism in cells exposed to hypoxia or ischaemia, trimetazidine prevents a decrease in intracellular ATP levels, thereby ensuring the proper functioning of ionic pumps and transmembrane sodium-potassium flow whilst maintaining cellular homeostasis.
Trimetazidine inhibits β-oxidation of fatty acids by blocking long-chain 3-ketoacyl-CoA thiolase, which enhances glucose oxidation. In an ischaemic cell, energy obtained during glucose oxidation requires less oxygen consumption than in the β-oxidation process. Potentiation of glucose oxidation optimizes cellular energy processes, thereby maintaining proper energy metabolism during ischaemia.
Pharmacodynamic Effects: In patients with ischaemic heart disease, trimetazidine acts as a metabolic agent, preserving the myocardial high-energy phosphate intracellular levels. Anti-ischaemic effects are achieved without concomitant haemodynamic effects.
Clinical Efficacy and Safety: Clinical studies have demonstrated the efficacy and safety of trimetazidine in the treatment of patients with chronic angina, either alone or when the benefit from other antianginal medicinal products was insufficient.
In a 426 patients randomized, double blind, placebo-controlled study (Trimpol-II), trimetazidine (60 mg/day) added to metoprolol 100mg daily (50 mg twice daily) for 12 weeks significantly improved statistically exercise tests parameters and clinical symptoms as compared to placebo: Total exercise duration 20.1 s, p=0.023, total workload 0.54 METs, p=0.001, time to 1-mm ST-segment depression 33.4 s, p=0.003, time to onset of angina 33.9 s, p<0.001, angina attacks/week -0.73, p=0.014 and short acting nitrates consumption/week, -0.63, p=0.032, without hemodynamic changes.
In a 223 patients randomized, double blind, placebo-controlled study (Sellier), one 35 mg trimetazidine modified release tablet (twice daily) added to 50 mg atenolol (once daily) for 8 weeks produced a significant increase (34.4 s, p=0.03) in the time to 1-mm ST-segment depression in exercise tests, in a subgroup of patients (n=173), when compared to placebo, 12 hours after taking the drug. A significant difference was also evidenced for the time to onset of angina pectoris (p=0.049). No significant difference between groups could be found for the other secondary endpoints (total exercise duration, total workload and clinical endpoints).
In a 1,962 patients 3-month randomised, double-blinded study (Vasco study) on top of atenolol 50 mg/d, 2 dosages of trimetazidine (70 mg/d and 140 mg/d) were tested versus placebo. In the overall population, including both asymptomatic and symptomatic patients, trimetazidine failed to demonstrate a benefit on both ergometric (total exercise duration, time to onset of 1mm ST and time to onset angina) and clinical endpoints. However, in the subgroup of symptomatic patients (n=1574) defined in a post-hoc analysis, trimetazidine (140 mg) significantly improved total exercise duration (23.8 s vs 13.1 s placebo; p=0.001) and time to onset of angina (46.3 s vs 32.5 s placebo; p=0.005).
Pharmacokinetics: After oral administration, maximum concentration is found, on average, 5 hours after taking the tablet. Over 24 hours the plasma concentration remains at levels ≥75% of the maximum concentration for 11 hours.
Steady state is reached by the 60th hour, at the latest.
The pharmacokinetic characteristics of Vastarel MR are not influenced by meals.
The apparent distribution volume is 4.8 L/kg; protein binding is low: In vitro measurements give value of 16%.
Trimetazidine is eliminated primarily in the urine, mainly in the unchanged form.
The elimination half-life of Vastarel MR is an average of 7 hours in healthy young volunteers and 12 hours in subjects aged >65 years. Total clearance of trimetazidine is the result of major renal clearance which is directly correlated to creatinine clearance and, to a lesser extent, to liver clearance which is reduced with age.
A specific clinical study carried out in an elderly population using a dosage of 2 tablets per day taken in 2 doses, analysed by a kinetic population method, showed an increase in plasma exposure which does not justify a dosage alteration.
Toxicology: Preclinical Safety Data: Not applicable.