Cabazitaxel

Cabazitaxel
Names
Trade namesJevtana
Other namesXRP-6258
IUPAC name
  • (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(Acetyloxy)-15-{[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoyl]oxy}-1-hydroxy-9,12-dimethoxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl benzoate
Clinical data
Drug classTaxane[1]
Side effectsLow red blood cells, low white blood cells, low platelets, diarrhea[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: D
  • US: N (Not classified yet)
    Routes of
    use    		Intravenous
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa611009
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: ℞-only
    • EU: Rx-only
    Chemical and physical data
    FormulaC45H57NO14
    Molar mass835.944 g·mol−1
    3D model (JSmol)
    SMILES
    • CC1=C2C(C(=O)C3(C(CC4C(C3C(C(C2(C)C)(CC1OC(=O)C(C(C5=CC=CC=C5)NC(=O)OC(C)(C)C)O)O)OC(=O)C6=CC=CC=C6)(CO4)OC(=O)C)OC)C)OC
    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, ☒N
    • Key:BMQGVNUXMIRLCK-OAGWZNDDSA-N checkY

    Cabazitaxel, sold under the brand name Jevtana, is a medication used to treat prostate cancer.[2] Specifically it is used for metastatic castration-resistant prostate cancer who have failed other treatment.[2] It is given by injection into a vein.[2]

    Common side effects include low red blood cells, low white blood cells, low platelets, and diarrhea.[2] Other side effects may include allergic reactions and kidney problems.[3] It is a taxane which interferes with microtubules.[1]

    Cabazitaxel was approved for medical use in the United States in 2010 and Europe in 2011.[3][2] In the United Kingdom 60 mg costs the NHS about £3,700 as of 2021.[4] This amount in the United States costs about 12,700 USD.[5]

    Medical uses

    Cabazitaxel in combination with prednisone is a treatment option for hormone-refractory prostate cancer following docetaxel-based treatment.

    Dosage

    There are many questions about the optimal use of cabazitaxel after the approval of using it in the treatment of docetaxel-refractory mCRPC. One question is about the optimal use. Concerning the significant myelosuppression during cabazitaxel administration at 25 mg/m2, a randomized phase III study will appraise the safety and efficacy of cabazitaxel at 20 mg/m2.  One more question is about the effectiveness and tolerability of cabazitaxel when it is administered with other therapies. A phase I/II trials are testing the co-administration of cabazitaxel with other therapies (e.g. abiraterone) and investigational agents (e.g. custirsen)[6]

    Side effects

    Common side effects include neutropenia (including febrile neutropenia) and GIT side effects appeared mainly in diarrhea, whereas, neuropathy was rarely detected.[7]

    Mechanism of action

    Taxanes enhance the microtubules stabilization and inhibit the 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]

    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.[10]

    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.[6]

    Research

    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.[11] 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%).[12]

    See also

    References

    1. 1 2 "Cabazitaxel". NCI Drug Dictionary. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. 2011-02-02. Archived from the original on 2015-04-25. Retrieved 2021-02-16.
    2. 1 2 3 4 5 6 "Jevtana". Archived from the original on 1 May 2021. Retrieved 29 December 2021.
    3. 1 2 "Cabazitaxel Monograph for Professionals". Drugs.com. Archived from the original on 2 November 2020. Retrieved 28 December 2021.
    4. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 968. ISBN 978-0857114105.
    5. ↑ "Jevtana Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 29 December 2021.
    6. 1 2 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.
    7. ↑ 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.
    8. ↑ 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.
    9. ↑ 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.
    10. ↑ 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.
    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. ↑ "Cabazitaxel Effective for Hormone Refractory Prostate Cancer After Failure of Taxotere".
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