Chemistry:Cabazitaxel

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Short description: Chemical compound
Cabazitaxel
Cabazitaxel.png
Clinical data
Trade namesJevtana
Other namesXRP-6258
AHFS/Drugs.comMonograph
MedlinePlusa611009
License data
Pregnancy
category
  • AU: D
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only [1]
  • EU: Rx-only
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC45H57NO14
Molar mass835.944 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Cabazitaxel, sold under the brand name Jevtana, is a semi-synthetic derivative of a natural taxoid.[2] It is a microtubule inhibitor,[1] and the fourth taxane to be approved as a cancer therapy.[citation needed]

Cabazitaxel was developed by Sanofi-Aventis and was approved by the U.S. Food and Drug Administration (FDA) for the treatment of hormone-refractory prostate cancer in June 2010.[3][4][5] It is available as a generic medication.[6][7]

Medical uses

Cabazitaxel is indicated in combination with prednisone for the treatment of metastatic castration-resistant prostate cancer following docetaxel-based treatment.[1]

Mechanism of action

Taxanes enhance microtubule stabilization and inhibit cellular mitosis and division.[8] Moreover, taxanes prevent androgen receptor (AR) signaling by binding cellular microtubules and the microtubule-associated motor protein dynein, thus averting AR nuclear translocation.[9]

Clinical trials

In patients with metastatic castration-resistant prostate cancer (mCRPC), overall survival (OS) is markedly enhanced with cabazitaxel versus mitoxantrone after prior docetaxel treatment. FIRSTANA (ClinicalTrials.gov identifier: NCT01308567) assessed whether cabazitaxel 20 mg/m2 (C20) or 25 mg/m2 (C25) is superior to docetaxel 75 mg/m2 (D75) in terms of OS in patients with chemotherapy-naïve mCRPC. However, C20 and C25 did not demonstrate superiority for OS versus D75 in patients with chemotherapy-naïve mCRPC. Cabazitaxel and docetaxel demonstrated different toxicity profiles, and C20 showed the overall lowest toxicity.[10] In a phase III trial with 755 men for the treatment of castration-resistant prostate cancer, median survival was 15.1 months for patients receiving cabazitaxel versus 12.7 months for patients receiving mitoxantrone. Cabazitaxel was associated with more grade 3–4 neutropenia (81.7%) than mitoxantrone (58%).[11] Common adverse effects with cabazitaxel include neutropenia (including febrile neutropenia) and GIT side effects appeared mainly in diarrhea, whereas, neuropathy was rarely detected.[12]

Pharmacokinetics

Cabazitaxel administration causes a decrease in plasma concentrations showing triphasic kinetics: a mean half life (t1/2) of 2.6 min in the first phase, a mean t1/2 of 1.3 h in the second phase, and a mean t1/2 of 77.3 h in the third phase.[13]

Metabolism

Cabazitaxel is basically metabolized in the liver by [cytochrome P450 (CYP)3A4/5 > CYP2C8], which result in seven plasma metabolites and excreted 20 metabolites. During 14 days after administration, 80% of cabazitaxel is excreted: 76% in the feces and 3.7% as a renal excretion.[14]

References

  1. ↑ 1.0 1.1 1.2 "Jevtana- cabazitaxel kit". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=de3d9c26-572b-4ea4-9b2d-dd58a2b3e8fa. 
  2. ↑ "Cabazitaxel". NCI Drug Dictionary. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. February 2, 2011. http://www.cancer.gov/drugdictionary/?CdrID=534131. 
  3. ↑ "Drug Approval Package: Jevtana (Cabazitaxel) NDA #201023". July 8, 2013. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/201023s000TOC.cfm. 
  4. ↑ "Jevtana (cabazitaxel) Injection Approved by U.S. FDA After Priority Review" (Press release). Sanofi Aventis. June 17, 2010. Retrieved December 30, 2021 – via PR Newswire.
  5. ↑ "Jevtana (cabazitaxel) Injection Approved by U.S. FDA After Priority Review - Jun 17, 2010" (Press release). Sanofi. June 17, 2010. Retrieved December 30, 2021.
  6. ↑ "Cabazitaxel: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=207949. 
  7. ↑ "First Generic Drug Approvals". October 17, 2022. https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals. 
  8. ↑ "Microtubules as a target for anticancer drugs". Nature Reviews. Cancer 4 (4): 253–65. April 2004. doi:10.1038/nrc1317. PMID 15057285. 
  9. ↑ "Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer". Cancer Research 71 (18): 6019–29. September 2011. doi:10.1158/0008-5472.CAN-11-1417. PMID 21799031. 
  10. ↑ "Cabazitaxel Versus Docetaxel As First-Line Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer: A Randomized Phase III Trial-FIRSTANA". Journal of Clinical Oncology 35 (28): 3189–3197. October 2017. doi:10.1200/JCO.2016.72.1068. PMID 28753384. 
  11. ↑ "Cabazitaxel Effective for Hormone Refractory Prostate Cancer After Failure of Taxotere". http://professional.cancerconsultants.com/oncology_main_news.aspx?id=44709. [yes|permanent dead link|dead link}}]
  12. ↑ "Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer". Drug Design, Development and Therapy 5: 117–24. March 2011. doi:10.2147/DDDT.S13029. PMID 21448449. 
  13. ↑ "Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors". Clinical Cancer Research 15 (2): 723–30. January 2009. doi:10.1158/1078-0432.CCR-08-0596. PMID 19147780. 
  14. ↑ "The role of cabazitaxel in the treatment of metastatic castration-resistant prostate cancer". Therapeutic Advances in Urology 6 (3): 97–104. June 2014. doi:10.1177/1756287214528557. PMID 24883107. 

External links



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