Mytrex Injection

Indications

• Malignant pleural mesothelioma (in combination with cisplatin)
• Locally advanced or metastatic non-small cell lung cancer (NSCLC) other than predominantly squamous cell histology (first-line therapy in combination with cisplatin)
• Second-line treatment of locally advanced or metastatic NSCLC (monotherapy)

Mechanism of action

Pemetrexed inhibits several folate-dependent enzymes, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). These enzymes are crucial for the de novo biosynthesis of thymidine and purine nucleotides. Upon entering the cell, pemetrexed is converted into polyglutamate forms by folylpolyglutamate synthetase, which are retained within the cell and act as potent inhibitors of TS and GARFT, prolonging the drug's action in tumor cells.

Pharmacodynamics

In vitro studies indicate that pemetrexed effectively inhibits the growth of mesothelioma cell lines, demonstrating synergistic effects when used in combination with cisplatin. The drug's pharmacodynamic effects correlate with systemic exposure, particularly the depth of the absolute neutrophil counts (ANC) nadir, which is influenced by the concurrent administration of folic acid and vitamin B12. Notably, there is no cumulative effect of pemetrexed on ANC nadir across multiple treatment cycles.

Pharmacokinetics

Pemetrexed is administered as a solution for infusion and is absorbed into cells via reduced folate carriers and membrane folate binding proteins. Once inside the cells, it undergoes polyglutamation, which enhances its retention and activity. The pharmacokinetic profile indicates that the drug has an extended intracellular half-life due to its polyglutamate forms, resulting in prolonged effects in malignant tissues. Its clearance and distribution are influenced by factors such as renal function and the use of folate supplementation.

Adverse effects

• Appetite decreased
• Fatigue
• Nausea
• Vomiting
• Diarrhea
• Anemia
• Neutropenia
• Thrombocytopenia
• Rash
• Stomatitis

Interactions

• Aspirin: Moderate (increases exposure)
• NSAIDs: Moderate (increases exposure)
• Pyrimethamine: Unknown (increases risk of adverse effects)
• Live vaccines: Unknown (increases risk of generalized infection, possibly life-threatening)

Precautions

• Prophylactic folic acid supplementation required
• History of diabetes
• History of cardiovascular disease

Pregnancy

Pemetrexed is not recommended during pregnancy due to potential harm to the fetus.

Breast-feeding

It is not known whether pemetrexed is excreted in human milk; caution is advised.

Storage

Store in the original container, protected from light. Once reconstituted, use immediately.

Formulations

• Pemetrexed 100 mg powder for concentrate for solution for infusion
• Pemetrexed 500 mg powder for concentrate for solution for infusion
• Pemetrexed 850 mg/34 ml concentrate for solution for infusion
• Pemetrexed 1 g/40 ml concentrate for solution for infusion

Mechanism of action

Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity 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), 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. Pemetrexed is an antifolate containing the pyrrolopyrimidine-based nucleus that exerts its antineoplastic activity 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), 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 folyl polyglutamate synthase. 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. ... Activity of the /pemetrexed/ may be partially preserved under conditions in which cells are highly resistant to other thymidylate synthase inhibitors, possibly because of premetrexed's secondary inhibitory effects on purine synthesis. ... Pemetrexed activity is modulated by natural folates within cells that compete for polyglutamation at the level of folylpolyglutamate synthetase. Cells resistant to methotrexate because of impaired transport via the reduced folate carrier may retain partial sensitivity to pemetrexed. This is due to concurrent diminished transport of physiologic reduced folates and contraction of the cellular folate pool, thereby relaxing the usual level of suppression of pemetrexed polyglutamation. The risk of pemetrexed toxicity is increased when cellular folates are suboptimal.

Pharmacodynamics

Pemetrexed inhibited the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) and showed synergistic effects when combined with cisplatin. Based on population pharmacodynamic analyses, the depth of the absolute neutrophil counts (ANC) nadir correlates with systemic exposure to pemetrexed and supplementation with folic acid and vitamin B12. There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.