Accord Pemetrexed

Accord Pemetrexed Mechanism of Action





Accord Healthcare
Full Prescribing Info
Pharmacotherapeutic Group: Folic acid analogues. ATC Code: L01BA04.
Pharmacology: Accord Pemetrexed is a multi-targeted anti-cancer antifolate agent that exerts its action by disrupting crucial folate dependent metabolic processes essential for cell replication.
Pemetrexed behaves as a multi-targeted antifolate by inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), which are key folate dependent enzymes for the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is rapidly and efficiently converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase.
The polyglutamate forms are retained in cells and are even more potent inhibitors of TS and GARFT. Polyglutamation is a time- and concentration-dependent process that occurs in tumour cells and, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
Pharmacokinetics: Pemetrexed has a steady-state volume of distribution of 9 L/m2. Binding is not notably affected by varying degrees of renal impairment. Pemetrexed undergoes limited hepatic metabolism. Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the administered dose being recovered unchanged in urine within the first 24 hours following administration. Pemetrexed total systemic clearance is 91.8mL/min and the elimination half-life from plasma is 3.5 hours in patients with normal renal function (creatinine clearance of 90ml/min). Pemetrexed total systemic exposure (AUC) and maximum plasma concentration increase proportionally with dose. The pharmacokinetics of pemetrexed are consistent over multiple treatment cycles.
The pharmacokinetic properties of pemetrexed are not influenced by concurrent administered cisplatin. Oral folic acid and intramuscular vitamin B12 supplementation do not affect the pharmacokinetics of pemetrexed.
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