Vastarel OD Mechanism of Action

Pharmacotherapeutic group: Other cardiac preparations. ATC code: C01EB15.
Pharmacology: Pharmacodynamics: Mechanism of action: Trimetazidine is an anti-ischemic (anti-anginal) metabolic agent, which improves myocardial glucose utilization through inhibition of long-chain 3-ketoacyl CoA thiolase activity, which results in a reduction in fatty acid oxidation and a stimulation of glucose oxidation. High fatty acid oxidation rates are detrimental during ischemia due to an inhibition of glucose oxidation leading to uncoupling of glycolysis and an increase in proton production, which has the potential to accelerate sodium and calcium overload in the heart, which leads to an exacerbation of ischemic injury and decreased cardiac efficiency during reperfusion.
In an ischaemic cell, 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-ischemic effects are achieved without concomitant haemodynamic effects.
Clinical efficacy and safety: Clinical studies on trimetazidine have demonstrated its efficacy and safety 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 100 mg daily (50 mg b.i.d) for 12 weeks significantly improved statistically exercise tests parameters and clinical symptoms as compared to placebo: total exercise duration +20.1s, p=0.023, total workload +0.54 METs, p=0.001, time to 1-mm ST-segment depression +33.4s, p=0.003, time to onset of angina +33.9s, 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 (b.i.d.) added to 50 mg atenolol (o.d.) for 8 weeks produced a significant increase (+34.4s, p=0.03) in the time to 1-mm ST-segment depression in exercise tests, in a sub-group 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 1962 patients three-month randomised, double-blinded study (Vasco study) on top of atenolol 50 mg/day, two dosages of trimetazidine (70 mg/day and 140 mg/day) 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 1 mm ST and time to onset angina) and clinical endpoints. However, in the subgroup of symptomatic patients (n=1574), trimetazidine (140 mg) significantly improved total exercise duration (+23.8s versus +13.1s placebo; p=0.001) and time to onset of angina (+46.3s versus +32.5s placebo; p=0.005).
In a 165 patients three-month randomised, double-blind acceptability study on top of both routine antianginal therapies and secondary prevention therapy, the safety profile of trimetazidine 80 mg once daily was shown to be similar to that of trimetazidine MR 35 mg bid. In the Safety Set, the rate of patients who experienced at least one EAE during the treatment period was slightly lower in the trimetazidine 80 mg group (17.1%) than in the trimetazidine MR 35 mg group (22.9%).
Overall, 6 patients in the Safety Set, experienced 9 serious adverse events (all were emergent) during the study without relevant difference between groups: 3 patients (3.7%) reported 6 serious EAEs in the trimetazidine 80 mg group (cardiac failure, acute myocardial infarction, ventricular fibrillation, blood pressure increased, renal colic and pulmonary oedema) and 3 patients (3.6%) in the trimetazidine MR 35 mg reported 3 serious EAEs (2 atrial fibrillations and one ischaemic stroke).
Regarding biochemical parameters, 8 emergent Potentially Clinically Significant Abnormal value (PCSA) were reported, sparse in both groups: one high GGT, one low clearance creatinine and one high triglycerides in the trimetazidine 80 mg group, and one high glucose, one low HDL-cholesterol and 3 high triglycerides in the trimetazidine MR 35 mg group; to note 1 high PCSA value of triglycerides in the trimetazidine 80 mg dose group versus 3 in the trimetazidine MR 35 mg group. Overall 2 patients had emergent haematological PCSA value: low platelets in the trimetazidine 80 mg group and high white blood cell count in the trimetazidine MR 35 mg group.
Pharmacokinetics: Absorption: After oral administration of trimetazidine 80 mg capsule, trimetazidine PK profile is flat with a peak of trimetazidine concentration reached around 14 hours after drug intake. Over dosing interval i.e. 24 hours the plasma concentration remains for 15 hours at levels above or equal to 75% of the maximum concentration. Steady state is reached by the third dose intake (3 days). [Audet D. Comparative pharmacokinetic study of one capsule of trimetazidine MR 80 mg o.d. versus one tablet of trimetazidine MR 35 mg b.i.d., after repeated oral administration.]
Food intake has no effect on trimetazidine PK after administration of the 80 mg formulation. [Audet D. Comparative pharmacokinetic study of one capsule of trimetazidine MR 80 mg o.d. in fasting conditions versus one capsule of trimetazidine MR 80 mg o.d., in fed conditions (high fat, high calorie breakfast), after one-day administration.]
Distribution: The volume of distribution is 4.8 l/kg; protein binding is low (16%).
Elimination: Trimetazidine is primarily eliminated in the urine, mainly as unchanged form. The elimination half-life is on average 7 hours in healthy young volunteers and 12 hours in elderly (more than 65 years).
Total body clearance of trimetazidine mainly consists of renal clearance which is directly correlated to creatinine clearance and, to a lesser extent, of liver clearance which is reduced with age.
Special populations: Elderly: The elderly may have increased trimetazidine exposure due to age-related decrease in renal function. A dedicated pharmacokinetic study performed in elderly 75-84 years or very elderly (≥85 years) participants showed that moderate renal impairment (creatinine clearance between 30 and 60 ml/min) increased respectively by 1.0 and 1.3 fold the trimetazidine exposure in comparison to younger participants (30-65 years) with moderate renal impairment.
A specific clinical study carried out in an elderly population (older than 75 years old) using a dosage of 2 tablets of trimetazidine MR 35 mg per day taken in 2 doses, analysed by a kinetic population method, showed on average a 2-fold increase in plasma exposure in patients with severe renal impairment (creatinine clearance below 30 ml/min) as compared to those with a creatinine clearance above 60 ml/min.
Renal impairment: Trimetazidine exposure is increased on average by 1.7-fold in patients with moderate renal impairment (creatinine clearance between 30 and 60 ml/min), and on average by 3.1-fold in patients with severe renal impairment (creatinine clearance below 30 ml/min) as compared to healthy volunteers, with normal renal function.
Paediatrics: The pharmacokinetics of trimetazidine has not been studied in children aged below 18 years and in adolescents.
Toxicology: Preclinical safety data: Chronic toxicity studies conducted by the oral route in dogs (5 to 40 mg.kg^-1.^d-1) and rats (5 to 200 mg.kg^-1.^d-1), showed a good safety profile.
Neither embryo-foetotoxic effect nor teratogenicity were detected in mice and in rabbits. A general study on reproduction and embryogenesis in 3 generations of rats showed no anomalies.
The genotoxic potential was thoroughly assessed with in vitro studies including the evaluation of the mutagenic and clastogenic potential and one in vivo study. All tests were negative.