Pemetrexed

Pemetrexed
Names
Trade namesAlimta, Pemfexy, Ciambra, others
IUPAC name
  • (2S)-2-{[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino}pentanedioic acid
Clinical data
Main usesMesothelioma, non-small cell lung cancer (NSCLC)[1]
Side effectsFever, infection, inflammation of the mouth, rash, nausea, tiredness, shortness of breath, chest pain[2]
Pregnancy
category
  • AU: D
  • US: N (Not classified yet)
    Routes of
    use    		Intravenous
    Typical dose500 mg/m2[2]
    External links
    AHFS/Drugs.comMonograph
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: ℞-only [3]
    • EU: Rx-only
    Pharmacokinetics
    BioavailabilityNA
    Protein binding81%
    MetabolismNegligible
    Elimination half-life3.5 hours
    ExcretionKidney
    Chemical and physical data
    FormulaC20H21N5O6
    Molar mass427.417 g·mol−1
    3D model (JSmol)
    SMILES
    • Nc3nc2[nH]cc(CCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)c2c(=O)[nH]3
    InChI
    • 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 checkY
    • Key:WBXPDJSOTKVWSJ-ZDUSSCGKSA-N checkY

    Pemetrexed, sold under the brand name Alimta among others, is a medication used to treat mesothelioma and non-small cell lung cancer (NSCLC).[1] It is used for mesothelioma which involves the pleura and cannot be removed by surgery.[2] It is given by gradual injection into a vein.[1]

    Common side effects include fever, infection, inflammation of the mouth, rash, nausea, tiredness, shortness of breath, and chest pain.[2] Other side effects may include bone marrow suppression.[2] Use in pregnancy may harm the baby.[2] It works by blocking the creation of DNA and RNA by inhibiting thymidylate transferase.[4][1]

    Pemetrexed was approved for medical use in the United States and Europe in 2004.[4][2] It is available as a generic medication.[1] In the United Kingdom 500 mg costs the NHS about £450 as of 2021.[1] This amount in the United States is about 3,700 USD.[5]

    Medical use

    It is used for the 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[6] in people whose disease is either unresectable or who are not otherwise candidates for curative surgery.[7] It is a first-line treatment, in combination with cisplatin, against locally advanced and metastatic non-small cell lung cancer (NSCLC) in people with non-squamous histology.[8][9][3]

    Carboplatin

    Pemetrexed is also recommended in combination with carboplatin and pembrolizumab for the first-line treatment of advanced non-small cell lung cancer.[10][11] 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.[12]

    Supplementation

    Patients are recommended to take folic acid and vitamin B12 supplement even if levels are normal when they are on pemetrexed therapy.[13][3] (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.[3]

    Dosage

    It is given at a dose of 500 mg/m2 every three weeks.[2]

    Side effects

    Pemetrexed, whether used alone or in combination with cisplatin, has these side effects:[3]

    Mechanism of action

    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[16][17] (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.

    History

    The molecular structure of pemetrexed was developed by Edward C. Taylor at Princeton University and clinically developed by Indianapolis-based drug maker, Eli Lilly and Company in 2004.

    It has been researched in the PARAMOUNT trial.

    Society and culture

    Trade names

    In addition to the brand name Alimta, this drug is also marketed in India by Abbott Healthcare as Pleumet and by Cadila Healthcare as Pemecad. In February 2020, Pemfexy was approved for use in the United States.[18]

    Cost

    In the United States, as of 2015, each vial of medicine costs between US$2,623 and US$3,100.[19]

    Research

    A Phase III study showed benefits of maintenance use of pemetrexed for non-squamous NSCLC.[20] Activity has been shown in malignant peritoneal mesothelioma.[21] Trials are currently testing it against esophageal cancer, chordoma[22] and other cancers.

    References

    1. 1 2 3 4 5 6 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 960. ISBN 978-0857114105.
    2. 1 2 3 4 5 6 7 8 "PEMEtrexed Monograph for Professionals". Drugs.com. Archived from the original on 20 April 2019. Retrieved 27 October 2021.
    3. 1 2 3 4 5 "Alimta- pemetrexed disodium injection, powder, lyophilized, for solution". DailyMed. 25 March 2020. Archived from the original on 20 October 2020. Retrieved 20 October 2020.
    4. 1 2 "Alimta". Archived from the original on 18 January 2021. Retrieved 27 October 2021.
    5. ↑ "Pemetrexed Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 27 October 2021.
    6. ↑ Manegold C (August 2003). "Pemetrexed (Alimta, MTA, multitargeted antifolate, LY231514) for malignant pleural mesothelioma". Semin. Oncol. 30 (4 Suppl 10): 32–6. doi:10.1016/S0093-7754(03)00283-5. PMID 12917819.
    7. ↑ National Cancer Institute: FDA Approval for Pemetrexed Disodium Archived 6 April 2015 at the Wayback Machine
    8. ↑ Cohen MH, Justice R, Pazdur R (September 2009). "Approval summary: pemetrexed in the initial treatment of advanced/metastatic non-small cell lung cancer". Oncologist. 14 (9): 930–5. doi:10.1634/theoncologist.2009-0092. PMID 19737998.
    9. ↑ 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): 141–9. doi:10.1016/j.lungcan.2009.06.006. PMID 19577816.
    10. ↑ Ettinger DS et al. NCCN Clinical Practice Guidelines in Oncology: Non-small Cell Lung Cancer V.2.2009 available from www.nccn.org
    11. ↑ Gandhi, Leena; Rodríguez-Abreu, Delvys; Gadgeel, Shirish; Esteban, Emilio; Felip, Enriqueta; De Angelis, Flávia; Domine, Manuel; Clingan, Philip; Hochmair, Maximilian J.; Powell, Steven F.; Cheng, Susanna Y.-S.; Bischoff, Helge G.; Peled, Nir; Grossi, Francesco; Jennens, Ross R.; Reck, Martin; Hui, Rina; Garon, Edward B.; Boyer, Michael; Rubio-Viqueira, Belén; Novello, Silvia; Kurata, Takayasu; Gray, Jhanelle E.; Vida, John; Wei, Ziwen; Yang, Jing; Raftopoulos, Harry; Pietanza, M. Catherine; Garassino, Marina C.; KEYNOTE-189 Investigators (2018). "Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer". New England Journal of Medicine. 378 (22): 2078–2092. doi:10.1056/NEJMoa1801005. hdl:10138/298862. PMID 29658856.
    12. ↑ Azzoli CG, Kris MG, Pfister DG (June 2007). "Cisplatin versus carboplatin for patients with metastatic non-small-cell lung cancer—an old rivalry renewed". J. Natl. Cancer Inst. 99 (11): 828–9. doi:10.1093/jnci/djk222. PMID 17551137.
    13. ↑ Hazarika M, White RM, Johnson JR, Pazdur R (2004). "FDA drug approval summaries: pemetrexed (Alimta)". Oncologist. 9 (5): 482–8. doi:10.1634/theoncologist.9-5-482. PMID 15477632.
    14. ↑ James P.; Wilmot Cancer Center. "Scientists Help Breast Cancer Survivor Lift the Fog of "Chemo Brain"" (PDF). Dialogue. University of Rochester Medical Center. Fall 2007: 2–3. Retrieved 1 December 2008.
    15. ↑ "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.
    16. ↑ McLeod HL, Cassidy J, Powrie RH, Priest DG, Zorbas MA, Synold TW, Shibata S, Spicer D, Bissett D, Pithavala YK, Collier MA, Paradiso LJ, Roberts JD (July 2000). "Pharmacokinetic and Pharmacodynamic Evaluation of the Glycinamide Ribonucleotide Formyltransferase Inhibitor AG2034". Clinical Cancer Research; Clinical Trials. 6 (7): 2677–84. PMID 10914709. Archived from the original on 28 July 2009. Retrieved 7 May 2021.
    17. ↑ Avendano, Carmen; Menendez, J. Carlos (April 2008). Medicinal Chemistry of Anticancer Drugs. Amsterdam: Elsevier. p. 37. ISBN 978-0-444-52824-7.
    18. ↑ "Pemfexy: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 19 October 2020. Retrieved 13 February 2020.
    19. ↑ Langreth, Robert (29 June 2016). "Decoding Big Pharma's Secret Drug Pricing Practices". Bloomberg. Archived from the original on 13 July 2016. Retrieved 15 July 2016.
    20. ↑ "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)". American Society of Clinical Oncology. Archived from the original on 16 June 2009. Retrieved 22 July 2009.
    21. ↑ Carteni G, Manegold C, Garcia GM, 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): 211–8. doi:10.1016/j.lungcan.2008.08.013. PMID 19042053.
    22. ↑ "Archive copy". Archived from the original on 25 April 2021. Retrieved 7 May 2021.{{cite web}}: CS1 maint: archived copy as title (link)
    Identifiers:
    • "Pemetrexed". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 19 May 2021. Retrieved 7 May 2021.
    • "Pemetrexed disodium". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 22 October 2020. Retrieved 7 May 2021.
    • "Pemetrexed disodium". NCI Drug Dictionary. National Cancer Institute. Archived from the original on 23 October 2020. Retrieved 7 May 2021.
    • "Pemetrexed disodium". National Cancer Institute. Archived from the original on 9 April 2021. Retrieved 7 May 2021.
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