Pemex Mechanism of Action

Pharmacology: Pemetrexed 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 such as 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, is thought to occur to a lesser extent, in normal tissues. Polyglutamated metabolites are thought to 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 MSTO-211H mesothelioma cell line showed synergistic effects when pemetrexed was combined concurrently with cisplatin.
Absolute neutrophil counts (ANC) following single-agent administration of ALIMTA 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 systemic exposure (AUC), varied between 8 to 9.6 days over a range of exposures from 38.3 to 316.8 mcg·hr/mL. Return to baseline ANC occurred 4.2 to 7.5 days after the nadir over the same range of exposures.
Pharmacokinetics: The following data are based on the results of studies conducted in foreign populations.
Absorption: The pharmacokinetics of ALIMTA 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 total systemic exposure (AUC) and maximum plasma concentration (Cmax) are increased proportionally with dose. The pharmacokinetics of pemetrexed do not change over multiple treatment cycles.
Distribution: 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.
Metabolism and Excretion: Pemetrexed is not metabolized to an appreciable extent and is primarily eliminated in the urine, with 70% to 90% of the dose recovered unchanged within the first 24 hours 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 half-life of Pemetrexed is 3.5 hours in patients with normal renal function (creatinine clearance of 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 of age on the pharmacokinetics of Pemetrexed was observed over a range of 26 to 80 years.
Effect of Gender: The pharmacokinetics of Pemetrexed were not different in male and female patients.
Effect of Race: The pharmacokinetics of Pemetrexed were similar in Caucasians and patients of African descent. Insufficient data are available to compare pharmacokinetics for other ethnic groups.
Effect of Hepatic Insufficiency: There was no effect of elevated AST, 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 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. (See Precautions and Dosage & Administration.)
Pediatric Patients: Pediatric patients were not included in clinical trials.
Effect of Ibuprofen: Ibuprofen doses of 400 mg four times a day reduce 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 (see Interactions).
Effect of Aspirin: Aspirin, administered in low to moderate doses (325 mg every 6 hours), 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: Coadministration of oral folic acid or intramuscular vitamin B₁₂ does not affect the pharmacokinetics of Pemetrexed.
Drugs Metabolized by Cytochrome P450 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.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m² basis) resulted in reduced fertility, hypospermia, and testicular atrophy.
See Precautions for male fertility patient use, and see Use in Pregnancy & Lactation for female patient use.