Pexitaz Mechanism of Action

Clinical Pharmacology: Pemetrexed is an antifolate containing the pyrrolopyrimidine based nucleus.
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 inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT), all folate dependent enzymes involved in 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 converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT. Polyglutamation is a time and concentration dependent process that occurs in tumor 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.
Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052). Studies with the MSTO211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.
Pharmacokinetics: The pharmacokinetics of pemetrexed administered as a single agent in doses ranging from 0.2 to 838 mg/m² infused over a 10 minute period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed undergoes limited metabolism in the liver. Results from in vitro studies with human liver microsomes indicated that pemetrexed would not be predicted to cause clinically significant inhibition of the metabolic clearance of drugs metabolised by CYP3A, CYP2D6, CYP2C9, and CYP1A2.
Pemetrexed is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours following administration. The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination half life of pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 90 mL/min). The clearance decreases, and exposure (AUC) increases, as renal function decreases. Pemetrexed total systemic exposure (AUC) and maximum plasma concentration (C_max) increase proportionally with dose. Between patient variability in clearance is moderate at 19.3%.
The pharmacokinetics of pemetrexed do not change over multiple treatment cycles. Pemetrexed has a steady state volume of distribution of 16.1 liters. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.
No effect of age on the pharmacokinetics of pemetrexed was observed over a range of 26 to 80 years. Pediatric patients were not included in clinical trials. The pharmacokinetics of pemetrexed were not different in male and female patients.
There was no effect of elevated AST (SGOT), ALT (SGPT), or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted. Pharmacokinetic analyses of pemetrexed included 127 patients with reduced renal function. Plasma clearance of pemetrexed decreases as renal function decreases, with a resultant increase in systemic exposure. Patients with creatinine clearances of 45, 50, and 80 mL/min had 65%, 54%, and 13% increases, respectively in pemetrexed total systemic exposure (AUC) compared to patients with creatinine clearance of 100 mL/ min.
Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed. Coadministration of oral folic acid or intramuscular vitamin B₁₂ does not affect the pharmacokinetics of pemetrexed.