Sign Out
Pharmacology: Pharmacodynamics: Preclinical studies have shown that pemetrexed inhibits the in vitro growth of mesothelioma cell lines (MSTO-211H. NCI-H2052). Studies with the MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.
Absolute neutrophil counts (ANC) following single-agent administration of pemetrexed to patients not receiving folic acid and vitamin B12 supplementation were characterized using population pharmacodynamic analyses. Severity of hematologic toxicity, as measured by the depth of the ANC nadir, correlates with the systemic exposure or area under the curve (AUC) of pemetrexed. It was also observed that lower ANC nadirs occurred in patients with elevated baseline cystathionine or homocysteine concentrations. The levels of these substances can be reduced by folic acid and vitamin B12 supplementation. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.
Time to ANC nadir with pemetrexed AUC, varied between 8-9.6 days over a range of exposures from 38-316 mcg/hr/mL. Return to baseline ANC occurred 4.2-7.5 days after the nadir over the same range of exposures.
Mechanism of Action: Pemetrexed for injection, is a folate analog metabolic inhibitor that exerts its action by disrupting 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) which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers eg, 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 retain in cells and are inhibitors of TS and GARFT. Polyglutamation is a time and concentration-dependent process that occurs in tumor cells and is thought to occur to a lesser extent in normal tissues. Polyglutamated metabolites are thought to have an increased intracellular half-life (t½) resulting in prolonged drug action in malignant cells.
Pharmacokinetics: Absorption: The pharmacokinetics of pemetrexed administered as a single-agent in doses ranging from 0.2-838 mg/m2 infused over a 10-min period have been evaluated in 426 cancer patients with a variety of solid tumors. Pemetrexed AUC and maximum plasma concentration (Cmax) increase proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles.
Distribution: Pemetrexed has a steady-state volume of distribution (Vss) of 16.1 L. In vitro studies indicate that pemetrexed is approximately 81% bound to plasma proteins. Binding is not affected by degree of renal impairment.
Metabolism and Excretion: Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70-90% of the dose recovered unchanged within the first 24 hrs following administration. The clearance decreases and exposure AUC increases, as renal function decreases. The total systemic clearance of pemetrexed is 91.8 mL/min and the elimination t½ of pemetrexed is 3.5 hrs in patient with normal renal function [creatinine clearance (CrCl) 90 mL/min].
The pharmacokinetics of pemetrexed in special populations were examined in about 400 patients in controlled and single-arm studies.
Effect of Age: No effect on age on the pharmacokinetics of pemetrexed was observed over a range of 26-80 years.
Effect of Hepatic Insufficiency: There was no effect of elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT) or total bilirubin on the pharmacokinetics of pemetrexed. However, studies of hepatically impaired patients have not been conducted.
Effect of Renal Insufficiency: 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 CrCl 45, 50 and 80 mL/min had 65%, 54% and 13% increases respectively in pemetrexed AUC compared to patients with CrCl 100 mL/min.
Effect of Ibuprofen: Ibuprofen doses of 400 mg 4 times a day reduces pemetrexed's clearance by about 20% (and increase AUC by 20%) in patients with normal renal function. The effect of greater doses of ibuprofen on pemetrexed pharmacokinetics is unknown.
Effect of Aspirin: Aspirin, administered in low to moderate doses (325 mg every 6 hrs) does not affect the pharmacokinetics of pemetrexed. The effect of greater doses of aspirin on pemetrexed pharmacokinetics is unknown.
Effect of Cisplatin: Cisplatin does not affect the pharmacokinetics of pemetrexed and the pharmacokinetics of total platinum are unaltered by pemetrexed.
Effect of Vitamins: Co-administration of oral folic acid or vitamin B12 IM does not affect the pharmacokinetics of pemetrexed.
Drugs Metabolized by Cytochrome P-450 Enzymes: Results from in vitro studies with human liver microsomes predict that pemetrexed would not cause clinically significant inhibition of metabolic clearance of drugs metabolized by CYP3A, CYP2D6, CYP2C9 and CYP1A2.
