What is Pemetrexed Disodium Hemipentahydrate?

Pemetrexed disodium hemipentahydrate, chemically known as N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-Glutamic acid disodium salt, 2.5 Hydrate (N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-Glutamic acid disodium salt, 2.5 Hydrate), has the following structure:

What is pemetrexed disodium hemipentahydrate used for?

Relevant Studies

• Pemetrexed disodium hemipentahydrate is an antimetabolic anticancer drug that inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and GARFT, originally developed by Eli Lilly in Indiana, USA under the brand name Alimta.
• In February 2004, it was approved by the FDA for use in combination with cisplatin for the first-line treatment of malignant pleural mesothelioma (MPM). Pemetrexed was the first drug approved by the FDA for the treatment of malignant pleural mesothelioma.
• In August 2004, it was approved by the FDA for second-line treatment of non-small cell lung cancer (NSCLC). The drug entered clinical use in China in 2004 and was marketed in 2005, with approved indications for MPM.

Applications

• For NSCLC Second-Line Treatment
• On August 19, 2004, Eli Lilly announced that the FDA approved pemetrexed disodium hemipentahydrate as a second-line treatment for locally advanced or metastatic NSCLC. Pemetrexed disodium hemipentahydrate is used as a monotherapy in second-line NSCLC chemotherapy due to its effectiveness and lower toxicity.
• Pemetrexed disodium hemipentahydrate has shown significant efficacy in various cell lines, including CCRF2CEM leukemia cells, GC3PC1 colon cancer cells, and HCF8 cecum cancer cells. Additionally, the drug is effective against high thymidylate synthase (TS) expressing MCFTDX and H630RIO cell lines, suggesting potential therapeutic benefits for tumors resistant to 5-FU and raltitrexed. Studies by Teicher et al. indicate that pemetrexed disodium hemipentahydrate has a synergistic effect when used in combination with 5-FU, outperforming the combination of 5-FU and MTX. Similarly, pemetrexed disodium hemipentahydrate demonstrates additive or synergistic effects when used with gemcitabine, platinum drugs, vinorelbine, paclitaxel, or CTX; moreover, using pemetrexed disodium hemipentahydrate before fractionated radiotherapy can enhance efficacy 2 to 3 times.
• For First-Line Treatment of Malignant Pleural Mesothelioma (MPM)
• Clinical trials have confirmed the efficacy of pemetrexed disodium hemipentahydrate. The trials compared treatment groups using pemetrexed disodium hemipentahydrate in combination with cisplatin against those using cisplatin alone. Results showed a median survival of 12.1 months for the combination therapy group, compared to 9.3 months for the cisplatin-only group, with a significant statistical difference. This was the first drug to significantly extend survival in malignant pleural mesothelioma patients, accelerating the FDA's clinical approval and marketing process for pemetrexed disodium hemipentahydrate. Research by Wang et al. discovered a high-affinity specific carrier in human malignant mesothelioma cell lines, which may help explain the drug's mechanism of action in treating malignant pleural mesothelioma.
• Pemetrexed disodium hemipentahydrate must be administered with vitamin B12 and folic acid supplements to reduce the incidence and severity of side effects.

How Does Pemetrexed Disodium Hemipentahydrate Work?

Pemetrexed disodium hemipentahydrate is a novel folate metabolism inhibitor with a pyrrolo[2,3-d]pyrimidine structure that simultaneously inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR), and GARFT, making it a multi-target folate antagonist. By interfering with folate-dependent metabolic pathways, it fundamentally inhibits cell replication, exerting its antitumor activity. Pemetrexed disodium hemipentahydrate is transported into cells via the reduced folate carrier (RFC) and folate transport membrane proteins (FPB). Once inside the cell, pemetrexed disodium hemipentahydrate is rapidly catalyzed by folate polyglutamate synthetase (FPGS) to form polyglutamate compounds. Both non-polyglutamated and polyglutamated pemetrexed disodium hemipentahydrate act as competitive inhibitors, affecting the activity of several folate-dependent enzymes, including key enzymes in nucleotide biosynthesis. This mechanism is similar to the inhibitory effects of methotrexate on TS and DHFR. Pemetrexed disodium hemipentahydrate and its polyglutamate derivatives competitively bind to various folate synthesis-related enzymes, which play critical roles in thymidylate and purine nucleotide biosynthesis. Due to its inhibition of multiple targets, pemetrexed disodium hemipentahydrate enhances its antitumor activity and has a lower likelihood of resistance development.

Advantages

Pemetrexed disodium hemipentahydrate, as a multi-target folate antagonist, has several advantages: (1) the drug targets multiple sites, reducing the likelihood of resistance; (2) the inhibition of multiple targets in the folate metabolism pathway during DNA synthesis may have additive or even synergistic effects; (3) differences in folate metabolism enzyme activities among various tumor cells affect the efficacy of anti-folate drugs, with multi-target drugs being less affected by these differences compared to single-target drugs. Based on the unique mechanism of action of pemetrexed disodium hemipentahydrate and its clinical research results expanding its indications, the drug has significant potential in the field of antitumor therapy and a broad prospect in tumor treatment applications.

Side Effects and Precautions of Pemetrexed Disodium Hemipentahydrate

The common side effects of pemetrexed disodium hemipentahydrate include hematologic toxicity, primarily neutropenia, which is often dose-limiting. Other frequent adverse effects include low white blood cell count, nausea, vomiting, fatigue, rash, and diarrhea. Additional adverse effects may include liver and kidney function abnormalities, vomiting, constipation, and chest pain. These symptoms may be indicative of bone marrow suppression-related infections caused by the drug.

Warnings

While pemetrexed disodium hemipentahydrate demonstrates significant efficacy in cancer treatment, its use must be tailored to individual patient conditions. Patients should always consult their physician when using this drug to ensure that the treatment plan is safe and effective, and to adjust the dosage and therapy according to medical advice. Professional medical guidance helps maximize the drug's therapeutic effects while minimizing potential side effects.

References

[3]https://go.drugbank.com/salts/DBSALT001782

[4]https://baike.baidu.com/item/%E5%9F%B9%E7%BE%8E%E6%9B%B2%E5%A1%9E%E4%BA%8C%E9%92%A0