Pexate 100/Pexate 500

Pexate 100/Pexate 500 Mechanism of Action







Full Prescribing Info
Pharmacology: Pharmacodynamics: Mechanism of Action: Pemetrexed is a multi-targeted anti-cancer antifolate agent that exerts its action by disrupting crucial folate-dependent metabolic processes essential for cell replication. In vitro studies have shown that 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 polyglutame forms by the enzyme folylpolyglutamate synthase. 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 tumor cells ad, to a lesser extent, in normal tissues. Polyglutamated metabolites have an increased intracellular half-life resulting in prolonged drug action in malignant cells.
Pharmacokinetics: The pharmacokinetic properties of Pemetrexed following single-agent administration have been evaluated in 426 cancer patients with a variety of solid tumors at doses ranging from 0.2 to 838 mg/m2 infused over a 10-minute period. Pemetrexed has a steady-state volume of distribution of 9 L/m2. In vitro studies indicate that Pemetrexed is approximately 81% bound to plasma proteins. Binding was 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 the urine within the first 24 hours following administration. Pemetrexed total systemic clearance 1s 91.8 mL/min and the elimination half-life from plasma is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). Between patient variability in clearance is moderate at 19.3%. 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 concurrently administered cisplatin. Oral folic acid and intramuscular vitamin B12 supplementation do not affect the pharmacokinetics of Pemetrexed.
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