Cabazitaxel

Cabazitaxel

Cabazitaxel

Chemical compound

Cabazitaxel, sold under the brand name Jevtana, is a semi-synthetic derivative of a natural taxoid.[3] It is a microtubule inhibitor,[2] and the fourth taxane to be approved as a cancer therapy.[citation needed]

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Cabazitaxel was developed by Sanofi-Aventis and was approved by the US Food and Drug Administration (FDA) for the treatment of hormone-refractory prostate cancer in June 2010.[4][5][6] It is available as a generic medication.[7][8]

Medical uses

Cabazitaxel is indicated in combination with prednisone for the treatment of metastatic castration-resistant prostate cancer following docetaxel-based treatment.[2]

Mechanism of action

Taxanes enhance microtubule stabilization and inhibit cellular mitosis and division.[9] Moreover, taxanes prevent androgen receptor (AR) signaling by binding cellular microtubules and the microtubule-associated motor protein dynein, thus averting AR nuclear translocation.[10]

Clinical trials

In people 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 people with chemotherapy-naïve mCRPC. Cabazitaxel and docetaxel demonstrated different toxicity profiles, and C20 showed the overall lowest toxicity.[11] In a phase III trial with 755 men for the treatment of castration-resistant prostate cancer, median survival was 15.1 months for participants receiving cabazitaxel versus 12.7 months for participants receiving mitoxantrone. Cabazitaxel was associated with more grade 3–4 neutropenia (81.7%) than mitoxantrone (58%).[12] Common adverse effects with cabazitaxel include neutropenia (including febrile neutropenia) and GIT side effects appeared mainly in diarrhea, whereas, neuropathy was rarely detected.[13]

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.[14]

Metabolism

Cabazitaxel is 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.[15]

References

  1. [1]
    "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved October 22, 2023.
  2. [2]
    "Jevtana- cabazitaxel kit". DailyMed. Retrieved December 30, 2021.
  3. [3]
    "Cabazitaxel". NCI Drug Dictionary. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. February 2, 2011.
  4. [4]
    "Drug Approval Package: Jevtana (Cabazitaxel) NDA #201023". U.S. Food and Drug Administration (FDA). July 8, 2013. Retrieved December 30, 2021.
  5. [5]
    "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.
  6. [6]
    "Jevtana (cabazitaxel) Injection Approved by U.S. FDA After Priority Review - Jun 17, 2010" (Press release). Sanofi. June 17, 2010. Retrieved December 30, 2021.
  7. [7]
    "Cabazitaxel: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved December 30, 2021.
  8. [8]
    "First Generic Drug Approvals". U.S. Food and Drug Administration. October 17, 2022. Retrieved November 28, 2022.
  9. [9]
    Jordan MA, Wilson L (April 2004). "Microtubules as a target for anticancer drugs". Nature Reviews. Cancer. 4 (4): 253–65. doi:10.1038/nrc1317. PMID 15057285. S2CID 10228718.
  10. [10]
    Darshan MS, Loftus MS, Thadani-Mulero M, Levy BP, Escuin D, Zhou XK, et al. (September 2011). "Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer". Cancer Research. 71 (18): 6019–29. doi:10.1158/0008-5472.CAN-11-1417. PMC 3354631. PMID 21799031.
  11. [11]
    Oudard S, Fizazi K, Sengeløv L, Daugaard G, Saad F, Hansen S, et al. (October 2017). "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. doi:10.1200/JCO.2016.72.1068. PMID 28753384.
  12. [12]
    "Cabazitaxel Effective for Hormone Refractory Prostate Cancer After Failure of Taxotere".[permanent dead link]
  13. [13]
    Paller CJ, Antonarakis ES (March 2011). "Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer". Drug Design, Development and Therapy. 5: 117–24. doi:10.2147/DDDT.S13029. PMC 3063116. PMID 21448449.
  14. [14]
    Mita AC, Denis LJ, Rowinsky EK, Debono JS, Goetz AD, Ochoa L, et al. (January 2009). "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. doi:10.1158/1078-0432.CCR-08-0596. PMID 19147780.
  15. [15]
    Tsao CK, Cutting E, Martin J, Oh WK (June 2014). "The role of cabazitaxel in the treatment of metastatic castration-resistant prostate cancer". Therapeutic Advances in Urology. 6 (3): 97–104. doi:10.1177/1756287214528557. PMC 4003844. PMID 24883107.
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