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Cabazitaxel

Clinical data
Trade names	Jevtana
Other names	XRP-6258
AHFS/Drugs.com	Monograph
MedlinePlus	a611009
License data	US DailyMed: Cabazitaxel
Pregnancy category	AU: D
Routes of administration	Intravenous
ATC code	L01CD04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: WARNINGRx-only EU: Rx-only
Identifiers
IUPAC name (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(Acetyloxy)-15-{amino}-2-hydroxy-3-phenylpropanoyl]oxy}-1-hydroxy-9,12-dimethoxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracycloheptadec-13-en-2-yl benzoate
CAS Number	183133-96-2
PubChem CID	9854073
IUPHAR/BPS	6798
DrugBank	DB06772
ChemSpider	8029779
UNII	51F690397J
KEGG	D09755 D10452
ChEBI	CHEBI:63584
ChEMBL	ChEMBL1201748
CompTox Dashboard (EPA)	DTXSID40171389
ECHA InfoCard	100.205.741
Chemical and physical data
Formula	C45H57NO14
Molar mass	835.944 g·mol
3D model (JSmol)	Interactive image
SMILES CO1C2OC2(OC(C)=O)2(OC(=O)c3ccccc3)3(O)C(OC(=O)(O)(NC(=O)OC(C)(C)C)c4ccccc4)C(C)=C((OC)C(=O)12C)C3(C)C
InChI InChI=1S/C45H57NO14/c1-24-28(57-39(51)33(48)32(26-17-13-11-14-18-26)46-40(52)60-41(3,4)5)22-45(53)37(58-38(50)27-19-15-12-16-20-27)35-43(8,36(49)34(55-10)31(24)42(45,6)7)29(54-9)21-30-44(35,23-56-30)59-25(2)47/h11-20,28-30,32-35,37,48,53H,21-23H2,1-10H3,(H,46,52)/t28-,29-,30+,32-,33+,34+,35-,37-,43+,44-,45+/m0/s1 Key:BMQGVNUXMIRLCK-OAGWZNDDSA-N
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Cabazitaxel, sold under the brand name Jevtana, is a semi-synthetic derivative of a natural taxoid. It is a microtubule inhibitor, and the fourth taxane to be approved as a cancer therapy.

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. It is available as a generic medication.

Medical uses

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

Mechanism of action

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

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/m (C20) or 25 mg/m (C25) is superior to docetaxel 75 mg/m (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. 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%). Common adverse effects with cabazitaxel include neutropenia (including febrile neutropenia) and GIT side effects appeared mainly in diarrhea, whereas, neuropathy was rarely detected.

Pharmacokinetics

Cabazitaxel administration causes a decrease in plasma concentrations showing triphasic kinetics: a mean half life (t_1/2) of 2.6 min in the first phase, a mean t_1/2 of 1.3 h in the second phase, and a mean t_1/2 of 77.3 h in the third phase.

Metabolism

Cabazitaxel is metabolized in the liver by , 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.

References

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. ^ "Jevtana- cabazitaxel kit". DailyMed. Retrieved December 30, 2021.
3. "Jevtana EPAR". European Medicines Agency (EMA). March 17, 2011. Retrieved August 10, 2024.
4. "Cabazitaxel". NCI Drug Dictionary. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. February 2, 2011.
5. "Drug Approval Package: Jevtana (Cabazitaxel) NDA #201023". U.S. Food and Drug Administration (FDA). July 8, 2013. Retrieved December 30, 2021.
6. "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.
7. "Jevtana (cabazitaxel) Injection Approved by U.S. FDA After Priority Review - Jun 17, 2010" (Press release). Sanofi. June 17, 2010. Retrieved December 30, 2021.
8. "Cabazitaxel: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved December 30, 2021.
9. "First Generic Drug Approvals". U.S. Food and Drug Administration. October 17, 2022. Retrieved November 28, 2022.
10. 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.
11. 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.
12. 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.
13. "Cabazitaxel Effective for Hormone Refractory Prostate Cancer After Failure of Taxotere".
14. 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.
15. 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.
16. 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.

External links

• Clinical trial number NCT00417079 for "XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC)" at ClinicalTrials.gov
• Clinical trial number NCT01308580 for "Cabazitaxel at 20 mg/m² Compared to 25 mg/m² With Prednisone for the Treatment of Metastatic Castration Resistant Prostate Cancer (PROSELICA)" at ClinicalTrials.gov
• Clinical trial number NCT02485691 for "Cabazitaxel Versus the Switch to Alternative AR-targeted Agent (Enzalutamide or Abiraterone) in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients Previously Treated With Docetaxel and Who Rapidly Failed a Prior AR-targeted Agent (CARD)" at ClinicalTrials.gov

• Medicine

• Microtubule inhibitors
• Mitotic inhibitors
• Carbamates
• Benzoate esters
• Acetate esters
• Taxanes
• Tert-Butyl esters