Pemetrexed

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Pemetrexed
Pemetrexed.svg
Pemetrexed ball-and-stick.png
Clinical data
Trade names Alimta, Pemfexy, Ciambra, others
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU:D
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability NA
Protein binding 81%
Metabolism Negligible
Elimination half-life 3.5 hours
Excretion Kidney
Identifiers
  • (2S)-2-{[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino}pentanedioic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.205.735 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H21N5O6
Molar mass 427.417 g·mol−1
3D model (JSmol)
  • Nc3nc2[nH]cc(CCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)c2c(=O)[nH]3
  • InChI=1S/C20H21N5O6/c21-20-24-16-15(18(29)25-20)12(9-22-16)6-3-10-1-4-11(5-2-10)17(28)23-13(19(30)31)7-8-14(26)27/h1-2,4-5,9,13H,3,6-8H2,(H,23,28)(H,26,27)(H,30,31)(H4,21,22,24,25,29)/t13-/m0/s1 Yes check.svgY
  • Key:WBXPDJSOTKVWSJ-ZDUSSCGKSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Pemetrexed, sold under the brand name Alimta among others, is a chemotherapy medication for the treatment of pleural mesothelioma and non-small cell lung cancer (NSCLC). [2] .

Contents

It is available as a generic medication. [6] [7]

Medical use

In February 2004, the U.S. Food and Drug Administration (FDA) approved pemetrexed for treatment of malignant pleural mesothelioma, a type of tumor of the mesothelium, the thin layer of tissue that covers many of the internal organs, in combination with cisplatin [8] for patients whose disease is either unresectable or who are not otherwise candidates for curative surgery. [9] In September 2008, the FDA granted approval as a first-line treatment, in combination with cisplatin, against locally advanced and metastatic non-small cell lung cancer (NSCLC) in patients with non-squamous histology. [10] [11] [2]

Carboplatin

Pemetrexed is also recommended in combination with carboplatin and pembrolizumab for the first-line treatment of advanced non-small cell lung cancer. [12] [13] However, the relative efficacy or toxicity of pemetrexed-cisplatin versus pemetrexed-carboplatin has not been established beyond what is generally thought about cisplatin or carboplatin doublet drug therapy. [14]

Supplementation

Patients are recommended to take folic acid and vitamin B12 supplement even if levels are normal when they are on pemetrexed therapy. [15] [2] (In clinical trials for mesothelioma, folic acid and B12 supplementation reduced the frequency of adverse events.) It is also recommended for patients to be on a glucocorticoid (e.g. dexamethasone) on the day prior, day of, and day after pemetrexed infusion to avoid skin rashes. [2]

Side effects

Pemetrexed, whether used alone or in combination with cisplatin, has these side effects: [2]

Mechanism of action

Pathway of tetrahydrofolate and antimetabolites Pathway of tetrahydrofolate and antimetabolites.pdf
Pathway of tetrahydrofolate and antimetabolites

Pemetrexed is chemically similar to folic acid and is in the class of chemotherapy drugs called folate antimetabolites. It works by inhibiting three enzymes used in purine and pyrimidine synthesis—thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase [18] [19] (GARFT). By inhibiting the formation of precursor purine and pyrimidine nucleotides, pemetrexed prevents the formation of DNA and RNA, which are required for the growth and survival of both normal cells and cancer cells.

Society and culture

Economics

In the United States, as of 2015, each vial of the medication costs between US$2,623 and US$3,100. [20]

Brand names

In February 2020, Pemfexy was approved for use in the United States. [21]

Research

A Phase III study showed benefits of maintenance use of pemetrexed for non-squamous NSCLC. [22] Activity has been shown in malignant peritoneal mesothelioma. [23]

Related Research Articles

<span class="mw-page-title-main">Mesothelioma</span> Cancer associated with asbestos

Mesothelioma is a type of cancer that develops from the thin layer of tissue that covers many of the internal organs. The area most commonly affected is the lining of the lungs and chest wall. Less commonly the lining of the abdomen and rarely the sac surrounding the heart, or the sac surrounding the testis may be affected. Signs and symptoms of mesothelioma may include shortness of breath due to fluid around the lung, a swollen abdomen, chest wall pain, cough, feeling tired, and weight loss. These symptoms typically come on slowly.

<span class="mw-page-title-main">Gefitinib</span> Medication used for cancer

Gefitinib, sold under the brand name Iressa, is a medication used for certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR, but resistances to gefitinib can arise through other mutations. It is marketed by AstraZeneca and Teva.

<span class="mw-page-title-main">Small-cell carcinoma</span> Type of malignant cancer

Small-cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tract. Compared to non-small cell carcinoma, small cell carcinoma is more aggressive, with a shorter doubling time, higher growth fraction, and earlier development of metastases.

<span class="mw-page-title-main">Carboplatin</span> Medication used to treat cancer

Carboplatin, sold under the brand name Paraplatin among others, is a chemotherapy medication used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It is used by injection into a vein.

Bevacizumab, sold under the brand name Avastin among others, is a monoclonal antibody medication used to treat a number of types of cancers and a specific eye disease. For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, lung cancer, ovarian cancer, glioblastoma, and renal-cell carcinoma. In many of these diseases it is used as a first-line therapy. For age-related macular degeneration it is given by injection into the eye (intravitreal).

Nicholas J. Vogelzang was a medical oncologist with Comprehensive Cancer Centers of Nevada (CCCN). He serves as medical director of the Research Executive Committee and Associate Chair of the Developmental Therapeutics and Genitourinary Committees for US Oncology Research. His research interests include clinical trials for genitourinary malignancies and mesothelioma.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Non-small-cell lung cancer</span> Any type of epithelial lung cancer other than small-cell lung carcinoma

Non-small-cell lung cancer (NSCLC), or non-small-cell lung carcinoma, is any type of epithelial lung cancer other than small-cell lung cancer (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to small-cell carcinoma. When possible, they are primarily treated by surgical resection with curative intent, although chemotherapy has been used increasingly both preoperatively and postoperatively.

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

Ramucirumab is a fully human monoclonal antibody (IgG1) developed for the treatment of solid tumors. This drug was developed by ImClone Systems Inc. It was isolated from a native phage display library from Dyax.

<span class="mw-page-title-main">Fosbretabulin</span> Chemical compound

Fosbretabulin is a microtubule destabilizing experimental drug, a type of vascular-targeting agent, a drug designed to damage the vasculature of cancer tumours causing central necrosis. It is a derivative of combretastatin. It is formulated as the salts fosbretabulin disodium and fosbretabulin tromethamine.

<span class="mw-page-title-main">Combined small-cell lung carcinoma</span> Medical condition

Combined small cell lung carcinoma is a form of multiphasic lung cancer that is diagnosed by a pathologist when a malignant tumor, arising from transformed cells originating in lung tissue, contains a component of;small cell lung carcinoma (SCLC), admixed with one components of any histological variant of non-small cell lung carcinoma (NSCLC) in any relative proportion.

Treatment of lung cancer refers to the use of medical therapies, such as surgery, radiation, chemotherapy, immunotherapy, percutaneous ablation, and palliative care, alone or in combination, in an attempt to cure or lessen the adverse impact of malignant neoplasms originating in lung tissue.

Targeted therapy of lung cancer refers to using agents specifically designed to selectively target molecular pathways responsible for, or that substantially drive, the malignant phenotype of lung cancer cells, and as a consequence of this (relative) selectivity, cause fewer toxic effects on normal cells.

<span class="mw-page-title-main">Crizotinib</span> ALK inhibitor for treatment of non-small-cell lung cancer

Crizotinib, sold under the brand name Xalkori among others, is an anti-cancer medication used for the treatment of non-small cell lung carcinoma (NSCLC). It acts as an ALK and ROS1 inhibitor.

<span class="mw-page-title-main">Nivolumab</span> Anticancer medication

Nivolumab, sold under the brand name Opdivo, is an anti-cancer medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction cancer. It is administered intravenously.

<span class="mw-page-title-main">Pembrolizumab</span> Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is administered by slow intravenous injection.

<span class="mw-page-title-main">PARAMOUNT trial</span> Clinical trial studying non-small-cell lung carcinoma

The PARAMOUNT trial is a clinical trial studying non-small-cell lung carcinoma (NSCLC). The trial was sponsored by Eli Lilly and Company and was conducted in several European countries and Canada. It was registered in November 2008 and was projected to end in September 2013.

<span class="mw-page-title-main">Atezolizumab</span> Monoclonal anti-PD-L1 antibody

Atezolizumab, sold under the brand name Tecentriq, is a monoclonal antibody medication used to treat urothelial carcinoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma, but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized, engineered monoclonal antibody of IgG1 isotype against the protein programmed cell death-ligand 1 (PD-L1).

Amivantamab, sold under the brand name Rybrevant, is a bispecific monoclonal antibody used to treat non-small cell lung cancer. Amivantamab is a bispecific epidermal growth factor (EGF) receptor-directed and mesenchymal–epithelial transition (MET) receptor-directed antibody. It is the first treatment for adults with non-small cell lung cancer whose tumors have specific types of genetic mutations: epidermal growth factor receptor (EGFR) exon 20 insertion mutations.

References

  1. ↑ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  2. 1 2 3 4 5 6 "Alimta- pemetrexed disodium injection, powder, lyophilized, for solution". DailyMed. 25 March 2020. Archived from the original on 20 October 2020. Retrieved 20 October 2020.
  3. ↑ "Pemfexy- pemetrexed injection". DailyMed. 20 January 2022. Archived from the original on 21 May 2022. Retrieved 20 May 2022.
  4. ↑ "Alimta EPAR". European Medicines Agency. 17 September 2018. Archived from the original on 18 January 2021. Retrieved 14 October 2022.
  5. ↑ "Pemetrexed Baxter: Pending EC decision". European Medicines Agency. 14 October 2022. Archived from the original on 14 October 2022. Retrieved 14 October 2022.
  6. ↑ "2022 First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). 3 March 2023. Archived from the original on 30 June 2023. Retrieved 30 June 2023.
  7. ↑ "Competitive Generic Therapy Approvals". U.S. Food and Drug Administration (FDA). 29 June 2023. Archived from the original on 29 June 2023. Retrieved 29 June 2023.
  8. ↑ Manegold C (August 2003). "Pemetrexed (Alimta, MTA, multitargeted antifolate, LY231514) for malignant pleural mesothelioma". Seminars in Oncology. 30 (4 Suppl 10): 32–36. doi:10.1016/S0093-7754(03)00283-5. PMID   12917819.
  9. ↑ National Cancer Institute: FDA Approval for Pemetrexed Disodium Archived 6 April 2015 at the Wayback Machine
  10. ↑ Cohen MH, Justice R, Pazdur R (September 2009). "Approval summary: pemetrexed in the initial treatment of advanced/metastatic non-small cell lung cancer". The Oncologist. 14 (9): 930–935. doi: 10.1634/theoncologist.2009-0092 . PMID   19737998. S2CID   28209589.
  11. ↑ Rossi A, Ricciardi S, Maione P, de Marinis F, Gridelli C (November 2009). "Pemetrexed in the treatment of advanced non-squamous lung cancer". Lung Cancer. 66 (2): 141–149. doi:10.1016/j.lungcan.2009.06.006. PMID   19577816.
  12. ↑ Ettinger DS, et al. "Non-small Cell Lung Cancer V.1.2007" (PDF). NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network (NCCN). Archived from the original (PDF) on 23 March 2007.
  13. ↑ Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. (KEYNOTE-189 Investigators) (May 2018). "Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer". The New England Journal of Medicine. 378 (22): 2078–2092. doi: 10.1056/NEJMoa1801005 . hdl: 10138/298862 . PMID   29658856.
  14. ↑ Azzoli CG, Kris MG, Pfister DG (June 2007). "Cisplatin versus carboplatin for patients with metastatic non-small-cell lung cancer--an old rivalry renewed". Journal of the National Cancer Institute. 99 (11): 828–829. doi: 10.1093/jnci/djk222 . PMID   17551137.
  15. ↑ Hazarika M, White RM, Johnson JR, Pazdur R (2004). "FDA drug approval summaries: pemetrexed (Alimta)". The Oncologist. 9 (5): 482–488. doi:10.1634/theoncologist.9-5-482. PMID   15477632. S2CID   11444611.
  16. ↑ "Scientists Help Breast Cancer Survivor Lift the Fog of "Chemo Brain"" (PDF). Dialogue. James P Wilmot Cancer Center, University of Rochester Medical Center: 2–3. Fall 2007. Retrieved 1 December 2008.[ permanent dead link ]
  17. ↑ "Oral Complications of Chemotherapy and Head/Neck Radiation". Cancer Topics – Coping with Cancer. National Cancer Institute. Archived from the original on 6 December 2008. Retrieved 1 December 2008.
  18. ↑ McLeod HL, Cassidy J, Powrie RH, Priest DG, Zorbas MA, Synold TW, et al. (July 2000). "Pharmacokinetic and pharmacodynamic evaluation of the glycinamide ribonucleotide formyltransferase inhibitor AG2034". Clinical Cancer Research. 6 (7): 2677–2684. PMID   10914709. Archived from the original on 28 July 2009. Retrieved 2 December 2008.
  19. ↑ Avendano C, Menendez JC (April 2008). Medicinal Chemistry of Anticancer Drugs. Amsterdam: Elsevier. p. 37. ISBN   978-0-444-52824-7.
  20. ↑ Langreth R (29 June 2016). "Decoding Big Pharma's Secret Drug Pricing Practices". Bloomberg. Archived from the original on 13 July 2016. Retrieved 15 July 2016.
  21. ↑ "Pemfexy: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 19 October 2020. Retrieved 13 February 2020.
  22. ↑ Belani CP, Brodowicz T, Ciuleanu T, Kim JH, Krzakowski M, Laack E, et al. (June 2009). "Maintenance pemetrexed (Pem) plus best supportive care (BSC) versus placebo (Plac) plus BSC: A randomized phase III study in advanced non-small cell lung cancer (NSCLC)". Journal of Clinical Oncology. 27 (18 suppl). American Society of Clinical Oncology: CRA8000. doi:10.1200/jco.2009.27.18_suppl.cra8000. Archived from the original on 16 June 2009. Retrieved 22 July 2009.
  23. ↑ Carteni G, Manegold C, Garcia GM, Siena S, Zielinski CC, Amadori D, et al. (May 2009). "Malignant peritoneal mesothelioma-Results from the International Expanded Access Program using pemetrexed alone or in combination with a platinum agent". Lung Cancer. 64 (2): 211–218. doi:10.1016/j.lungcan.2008.08.013. PMID   19042053.
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