Oxaliplatin

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Oxaliplatin
Oxaliplatin-2D-skeletal.svg
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Clinical data
Trade names Eloxatin
AHFS/Drugs.com Monograph
MedlinePlus a607035
License data
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Complete
Elimination half-life ~10 – 25 minutes [4]
Excretion Kidney
Identifiers
  • [(1R,2R)-cyclohexane-1,2-diamine](ethanedioato-O,O')platinum(II)
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
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Chemical and physical data
Formula C8H14N2O4Pt
Molar mass 397.294 g·mol−1
3D model (JSmol)
  • O1C(=O)C(=O)O[Pt-2]12[NH2+]C0CCCCC0[NH2+]2
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Oxaliplatin, sold under the brand name Eloxatin among others, is a cancer medication (platinum-based antineoplastic class) used to treat colorectal cancer. [5] It is given by injection into a vein. [5]

Contents

Common side effects include numbness, feeling tired, nausea, diarrhea, and low blood cell counts. [5] [6] Other serious side effects include allergic reactions. [6] [5] Use in pregnancy is known to harm the baby. [5] Oxaliplatin is in the platinum-based antineoplastic family of medications. [7] It is believed to work by blocking the duplication of DNA. [5]

Oxaliplatin was patented in 1976 in Japan and approved for medical use in 1996 in Europe. [8] It is on the 2023 World Health Organization's List of Essential Medicines. [9]

Medical uses

Oxaliplatin is used for treatment of colorectal cancer, typically along with folinic acid (leucovorin) and fluorouracil in a combination known as FOLFOX [10] or along with capecitabine in a combination known as CAPOX [11] or XELOX. [12] It may also be effective against breast cancer, germ cell tumor, ovarian cancer, non-small-cell lung cancer, and pancreatic cancer. [13]

Advanced colorectal cancer

Oxaliplatin by itself has modest activity against advanced colorectal cancer. [14] When compared with just 5-fluorouracil and folinic acid administered according to the de Gramont regimen, a FOLFOX4 regime produced no significant increase in overall survival, but did produce an improvement in progression-free survival, the primary end-point of the phase III randomized trial. [15]

Adverse effects

Side-effects of oxaliplatin treatment can potentially include:

In addition, some patients may experience an allergic reaction to platinum-containing drugs. This is more common in women. [19]

Oxaliplatin has less ototoxicity and nephrotoxicity than cisplatin and carboplatin. [16]

Structure and mechanism

The compound features a square planar platinum(II) center. In contrast to other drugs of the platinum-based antineoplastic class of drugs cisplatin and carboplatin, oxaliplatin features the bidentate ligand trans-1,2-diaminocyclohexane in place of the two monodentate ammine ligands. It also features a bidentate oxalate group. [7] The three-dimensional structure of the molecule has been elucidated by X-ray crystallography, although the presence of pseudosymmetry in the crystal structure has caused confusion in its interpretation. [22]

According to in vivo studies, oxaliplatin fights carcinoma of the colon through non-targeted cytotoxic effects. Like other platinum compounds, its cytotoxicity is thought to result from inhibition of DNA synthesis in cells. In particular, oxaliplatin forms both inter- and intra-strand cross links in DNA, [23] which prevent DNA replication and transcription, causing cell death.

History

Oxaliplatin was first synthesized in 1978 at Nagoya City University by Yoshinori Kidani. [24] It was later developed in Europe as a less toxic and more effective alternative to cisplatin. It gained European approval in 1996, [25] and approval by the U.S. Food and Drug Administration in 2002. [26] Generic oxaliplatin was first approved in the United States in August 2009. [27] Patent disputes caused generic production to stop in 2010, but it restarted in 2012. [28] [29]

Patent information

Eloxatin was covered by patent numbers 5338874 (expired 7 April 2013), 5420319 (expired 8 August 2016), 5716988 (expired 7 August 2015) and 5290961 (expired 12 January 2013) (see Electronic Orange Book patent info for Eloxatin). [30] Exclusivity code I-441, which expired on 4 November 2007, is for use combination with infusional 5-FU/LV for adjuvant treatment stage III colon cancer patients who have undergone complete resection primary tumor-based on improvement in disease free survival with no demonstrated benefit overall survival after 4 years. Exclusivity code NCE, New Chemical Entity, expired on 9 August 2007. [30]

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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. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  3. ↑ "Eloxatin- oxaliplatin injection, solution, concentrate". DailyMed. 22 October 2019. Retrieved 26 May 2022.
  4. ↑ Ehrsson H, Wallin I, Yachnin J (2002). "Pharmacokinetics of oxaliplatin in humans". Medical Oncology. 19 (4): 261–265. doi:10.1385/MO:19:4:261. PMID   12512920. S2CID   1068099.
  5. 1 2 3 4 5 6 "Oxaliplatin". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
  6. 1 2 Oun R, Moussa YE, Wheate NJ (May 2018). "The side effects of platinum-based chemotherapy drugs: a review for chemists". Dalton Transactions. 47 (19): 6645–6653. doi:10.1039/c8dt00838h. PMID   29632935.
  7. 1 2 Apps MG, Choi EH, Wheate NJ (August 2015). "The state-of-play and future of platinum drugs". Endocrine-Related Cancer. 22 (4): R219–R233. doi: 10.1530/ERC-15-0237 . hdl: 2123/24426 . PMID   26113607.
  8. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 513. ISBN   9783527607495. Archived from the original on 20 December 2016.
  9. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  10. ↑ "FOLFOX". National Cancer Institute. 18 September 2009. Retrieved 26 May 2022.
  11. ↑ "CAPOX". National Cancer Institute. 4 April 2012. Retrieved 26 May 2022.
  12. ↑ "XELOX". National Cancer Institute. 6 January 2012. Retrieved 26 May 2022.
  13. ↑ Townsend D (2007). "Oxaliplatin". xPharm: The Comprehensive Pharmacology Reference. Elsevier. pp. 1–4. doi:10.1016/B978-008055232-3.62973-3. ISBN   9780080552323.
  14. ↑ Bécouarn Y, Ychou M, Ducreux M, Borel C, Bertheault-Cvitkovic F, Seitz JF, et al. (August 1998). "Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers". Journal of Clinical Oncology. 16 (8): 2739–2744. doi:10.1200/JCO.1998.16.8.2739. PMID   9704726.
  15. ↑ de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. (August 2000). "Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer". Journal of Clinical Oncology. 18 (16): 2938–2947. doi:10.1200/JCO.2000.18.16.2938. PMID   10944126.
  16. 1 2 Pasetto LM, D'Andrea MR, Rossi E, Monfardini S (August 2006). "Oxaliplatin-related neurotoxicity: how and why?". Critical Reviews in Oncology/Hematology. 59 (2): 159–168. doi:10.1016/j.critrevonc.2006.01.001. PMID   16806962.
  17. ↑ Webster RG, Brain KL, Wilson RH, Grem JL, Vincent A (December 2005). "Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage-gated sodium channels". British Journal of Pharmacology. 146 (7): 1027–1039. doi:10.1038/sj.bjp.0706407. PMC   1751225 . PMID   16231011.
  18. ↑ Gebremedhn EG, Shortland PJ, Mahns DA (April 2018). "The incidence of acute oxaliplatin-induced neuropathy and its impact on treatment in the first cycle: a systematic review". BMC Cancer. 18 (1): 410. doi: 10.1186/s12885-018-4185-0 . PMC   5897924 . PMID   29649985.
  19. 1 2 Chay WY, Chew L, Yeoh TT, Tan MH (May 2010). "An association between transient hypokalemia and severe acute oxaliplatin-related toxicity predominantly in women". Acta Oncologica. 49 (4): 515–517. doi: 10.3109/02841860903464015 . PMID   20092386. S2CID   33026126.
  20. ↑ "Oxaliplatin Side Effects". Drugs.com. Archived from the original on 5 September 2014. Retrieved 5 September 2014.
  21. ↑ "Eloxatin information". mein.sanofi.de (in German). Archived from the original on 27 August 2016. Retrieved 15 June 2016.
  22. ↑ Johnstone TC (January 2014). "The Crystal Structure of Oxaliplatin: A Case of Overlooked Pseudo Symmetry". Polyhedron. 67: 429–435. doi:10.1016/j.poly.2013.10.003. PMC   3885251 . PMID   24415827.
  23. ↑ Graham J, Mushin M, Kirkpatrick P (January 2004). "Oxaliplatin". Nature Reviews. Drug Discovery. 3 (1): 11–12. doi:10.1038/nrd1287. PMID   14756144.
  24. ↑ Pizarro AM, Barry NP, Sadler PJ (2013). "3.25 - Metal–DNA Coordination Complexes". Comprehensive Inorganic Chemistry II (2nd ed.). Elsevier. pp. 751–784. doi:10.1016/B978-0-08-097774-4.00330-2. ISBN   9780080965291.
  25. ↑ Janjan NA, Delclos ME, Crane CH, Krishnan S, Das P (2010). "Chapter 24 - The Colon and Rectum". Radiation Oncology (9th ed.). Mosby. pp. 560–605. ISBN   978-0-323-04971-9.
  26. ↑ "Eloxatin FDA Approval History". Drugs.com.
  27. ↑ "Generic Eloxatin availability". Drugs.com. Archived from the original on 7 June 2013. Retrieved 19 April 2014.
  28. ↑ "Hospira Announces U.S. Re-Launch Of Generic Oxaliplatin Injection" (Press release). Archived from the original on 24 September 2015. Retrieved 25 August 2015.
  29. ↑ "Top 10 best-selling cancer drugs: Eloxatin–$1.2 billion". FiercePharma. 15 May 2012. Archived from the original on 21 April 2014. Retrieved 20 April 2014.
  30. 1 2 "Patent and Exclusivity Search Results from query on Appl No 021759 Product 001 in the OB_Rx list". Orange Book. U.S. Food and Drug Administrartion. Archived from the original on 26 September 2007.. Accessed on: 22 July 2007.

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