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Pharmacology: Pharmacodynamics: By preserving energy metabolism in cells exposed to hypoxia or ischemia, 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 ischemic 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 ischemia.
In patients with ischemic heart disease, trimetazidine acts as a metabolic agent, preserving the myocardial high-energy phosphate intracellular levels. Anti-ischemic effects are achieved without concomitant hemodynamic effects.
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). Food intake has no effect on trimetazidine PK after administration of the 80 mg formulation.
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 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 (≥85years) 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, analyzed 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.
No safety concern was observed in the elderly population as compared to the general population.
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.
No safety concern was observed in this population as compared to the general population.
Pediatrics: The pharmacokinetics of trimetazidine has not been studied in the pediatric population (<18 years old).
