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 ion 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 optimises 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 in combination with other antianginal treatments in poorly controlled patients.
In a 426-patient, randomised, 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 statistically significantly improved 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, frequency of angina attacks/week -0.73, p=0.014 and short acting nitrates consumption/week, -0.63, p=0.032, without haemodynamic changes.
In a 223-patient, randomised, 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 (+34.4 s, 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-patient, three-month, randomised, double blind 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 1-mm ST depression and time to onset of 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 (+43.6 s versus +32.5 s placebo; p=0.005).
Pharmacokinetics: Absorption: After oral administration, absorption of trimetazidine is rapid and the plasma peak is reached in less than 2 hours.
After a single oral dose of 20 mg of trimetazidine, the peak plasma concentration is approximately 55 ng.ml-1.
During repeated administration, the steady state is reached after 24 to 36 hours and remains very stable throughout treatment.
Distribution: The apparent distribution volume is 4.8 l/kg, which suggests good tissue diffusion. Protein binding is low: in vitro measurements give a value of 16%.
Elimination: Trimetazidine is eliminated primarily in the urine, mainly in the unchanged form.
The mean elimination half-life is 6 hours.
Linearity: Trimetazidine pharmacokinetics is linear following single dose administration up to 100 mg. Repeated doses showed a time-linear pharmacokinetic response.
Special populations: Elderly subjects: Trimetazidine exposure may be increased in elderly patients due to an age-related decrease in renal function. A pharmacokinetics study performed specifically in elderly (75-84 years) and very elderly (≥ 85 years) participants showed that in the event of moderate renal impairment (creatinine clearance between 30 and 60 ml/min) trimetazidine exposure was increased by a factor of 1.0 and 1.3, respectively in comparison with younger participants (30-65 years) with moderate renal impairment. No safety concerns were observed in the elderly subjects as compared with the general population.
Renal impairment: On average, trimetazidine exposure is multiplied by 1.7 in patients with moderate renal impairment (creatinine clearance between 30 and 60 ml/min) and by 3.1 in patients with severe renal impairment (creatinine clearance below 30 ml/min) compared with 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 have not been studied in the paediatric population (< 18 years).
Toxicology: Preclinical safety data: Chronic oral toxicity studies in dogs and rats showed a good safety profile.
Genotoxic potential was assessed in in vitro studies, including evaluation of the mutagenic and clastogenic potential, and in one in vivo study. All the tests were negative.
Reproductive toxicity studies performed in mice, rabbits and rats showed no embryotoxicity or teratogenicity. In rats, fertility was not impaired and no effects on postnatal development were observed.