Cabazitaxel

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Cabazitaxel
Cabazitaxel.png
Clinical data
Trade namesJevtana
AHFS/Drugs.comConsumer Drug Information
MedlinePlusa611009
License data
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
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DrugBank
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UNII
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ECHA InfoCard100.205.741 Edit this at Wikidata
Chemical and physical data
FormulaC45H57NO14
Molar mass835.93 g/mol g·mol−1
3D model (JSmol)
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Cabazitaxel (previously XRP-6258, trade name Jevtana) is a semi-synthetic derivative of a natural taxoid.[1] It was developed by Sanofi-Aventis and was approved by the U.S. FDA for the treatment of hormone-refractory prostate cancer on June 17, 2010. It is a microtubule inhibitor, and the fourth taxane to be approved as a cancer therapy.[2][unreliable source?]

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

Mechanism of action[edit]

Taxanes enhance the microtubules stabilization and inhibit the cellular mitosis and division.[3] Moreover, taxanes prevent androgen receptor (AR) signaling by binding cellular microtubules and the microtubule-associated motor protein dynein, thus averting AR nuclear translocation.[4]

Clinical trials[edit]

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.[5] 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%).[6] Common adverse effects with cabazitaxel include neutropenia (including febrile neutropenia) and GIT side effects appeared mainly in diarrhea, whereas, neuropathy was rarely detected.[7]

Pharmacokinetics[edit]

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.[8]

Metabolism[edit]

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.[9]

Dosing of Cabazitaxel[edit]

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)[9]

See also[edit]

References[edit]

  1. ^ http://www.cancer.gov/drugdictionary/?CdrID=534131
  2. ^ "Jevtana (cabazitaxel) Injection Approved by U.S. FDA After Priority Review" (Press release). sanofi-aventis. 2010-06-17. Retrieved June 17, 2010.
  3. ^ Leslie Wilson; Jordan, Mary Ann (April 2004). "Microtubules as a target for anticancer drugs". Nature Reviews Cancer. 4 (4): 253–265. doi:10.1038/nrc1317. ISSN 1474-1768.
  4. ^ Darshan, M. S.; Loftus, M. S.; Thadani-Mulero, M.; Levy, B. P.; Escuin, D.; Zhou, X. K.; Gjyrezi, A.; Chanel-Vos, C.; Shen, R. (2011-09-15). "Taxane-Induced Blockade to Nuclear Accumulation of the Androgen Receptor Predicts Clinical Responses in Metastatic Prostate Cancer". Cancer Research. 71 (18): 6019–6029. doi:10.1158/0008-5472.CAN-11-1417. ISSN 0008-5472. PMC 3354631. PMID 21799031.
  5. ^ Oudard, Stéphane; Fizazi, Karim; Sengeløv, Lisa; Daugaard, Gedske; Saad, Fred; Hansen, Steinbjørn; Hjälm-Eriksson, Marie; Jassem, Jacek; Thiery-Vuillemin, Antoine; Caffo, Orazio; Castellano, Daniel; Mainwaring, Paul N.; Bernard, John; Shen, Liji; Chadjaa, Mustapha; Sartor, Oliver (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.
  6. ^ "Cabazitaxel Effective for Hormone Refractory Prostate Cancer After Failure of Taxotere".[permanent dead link]
  7. ^ Paller, C. J.; Antonarakis, E. S. (2011). "Cabazitaxel: A novel second-line treatment for metastatic castration-resistant prostate cancer". Drug Design, Development and Therapy. 5: 117–124. doi:10.2147/DDDT.S13029. PMC 3063116. PMID 21448449.
  8. ^ Mita, A. C.; Denis, L. J.; Rowinsky, E. K.; DeBono, J. S.; Goetz, A. D.; Ochoa, L.; Forouzesh, B.; Beeram, M.; Patnaik, A. (2009-01-15). "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): 723–730. doi:10.1158/1078-0432.CCR-08-0596. ISSN 1078-0432. PMID 19147780.
  9. ^ a b Tsao, Che-Kai; Cutting, Elena; Martin, Jacob; Oh, William K. (2014-03-24). "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. ISSN 1756-2872. PMC 4003844. PMID 24883107.

External links[edit]