Pharmacotherapeutic Group: OTHER CARDIOVASCULAR ANTIANGINAL DRUG. ATC Code: C01EB15 (C: cardiovascular system).
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-ischemic 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, when the benefit from other antianginal medicinal products was insufficient.
In a 426-patients randomized, double blind, placebo-controlled study (TRIMPOL-II), trimetazidine (60mg/day) added to metoprolol 100mg 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/d, two 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 versus +13.1 s placebo; p=0.001) and time to onset of angina (+46.3 s versus +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 above or equal to 75% of the maximum concentration for 11 hours.
Steady state is reached by the 60th hour, at the latest.
The pharmacokinetic characteristics of Vastarel 35mg 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 35mg is an average of 7 hours in healthy young volunteers and 12 hours in subjects aged more than 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.
Special populations: Elderly subjects: 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 population pharmacokinetics approach, showed an increase in plasma exposure.
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.
Renal impairment: Trimetazidine exposure is increased on average by 1.7 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 young volunteers, with normal renal function. No safety concerns were observed in this population as compared with the general population.
Paediatric population: The pharmacokinetics of trimetazidine has not been studied in the paediatric population (<18 years).
Toxicology: Preclinical safety data: Chronic toxicity studies conducted by the oral route in dogs and rats, showed a good safety profile.
The genotoxic potential was assessed in in vitro studies, including evaluation of the mutagenic and clastogenic potential, and one in vivo study. All the tests were negative.
Reproductive toxicity studies in mice, rabbits and rats showed no embryotoxicity or teratogenicity. In rats, fertility was not impaired and there was no effects on postnatal development.