Cabazitaxel

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Cabazitaxel
Cabazitaxel.png
Names
Trade namesJevtana
Other namesXRP-6258
  • (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]
Pregnancy
category
  • AU: D
  • US: N (Not classified yet)
Routes of
use
Intravenous
External links
AHFS/Drugs.comMonograph
US NLMCabazitaxel
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)
  • 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=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. 1.0 1.1 "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. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Jevtana". Archived from the original on 1 May 2021. Retrieved 29 December 2021.
  3. 3.0 3.1 "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. 6.0 6.1 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".[permanent dead link]

External links

Identifiers: