Cabazitaxel

Các tên gọi khác (4 ) :

Cabazitaxelum
Taxoid XRP6258
TXD258
XRP6258

Thuốc điều trị ung thư

Thuốc Gốc

Small Molecule

CAS: 183133-96-2

ATC: L01CD04

CTHH: C₄₅H₅₇NO₁₄

PTK: 835.9324

Cabazitaxel is an anti-neoplastic used with the steroid medicine prednisone. Cabazitaxel is used to treat people with prostate cancer that has progressed despite treatment with docetaxel. Cabazitaxel is prepared by semi-synthesis with a precursor extracted from yew needles (10-deacetylbaccatin III). It was approved by the U.S. Food and Drug Administration (FDA) on June 17, 2010.

Nhận Dạng Quốc Tế & Đặc Tính Hóa Học

Công thức hóa học

C₄₅H₅₇NO₁₄

Phân tử khối

835.9324

Monoisotopic mass

835.377905537

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

InChI Key

InChIKey=BMQGVNUXMIRLCK-OAGWZNDDSA-N

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[11.3.1.0^{3,10}.0^{4,7}]heptadec-13-en-2-yl benzoate

Traditional IUPAC Name

(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetyloxy)-15-{[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl]oxy}-1-hydroxy-9,12-dimethoxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0^{3,10}.0^{4,7}]heptadec-13-en-2-yl benzoate

SMILES

[H][C@@](O)([C@@H](NC(=O)OC(C)(C)C)C1=CC=CC=C1)C(=O)O[C@@]1([H])C[C@@]2(O)[C@@]([H])(OC(=O)C3=CC=CC=C3)[C@]3([H])[C@@]4(CO[C@]4([H])C[C@]([H])(OC)[C@@]3(C)C(=O)[C@]([H])(OC)C(=C1C)C2(C)C)OC(C)=O

Độ hòa tan

4.13e-03 g/l

logP

4.2

logS

-5.3

pKa (strongest acidic)

11.97

pKa (Strongest Basic)

-3.6

PSA

202.45 Å²

Refractivity

213.4 m³·mol^-1

Polarizability

86.39 Å³

Rotatable Bond Count

H Bond Acceptor Count

H Bond Donor Count

Physiological Charge

Number of Rings

Bioavailability

MDDR-Like Rule

true

Dược Lực Học : Cabaitaxel has anti-tumour properties and is effective against docetaxel-sensitive and -insensitive tumours.

Cơ Chế Tác Dụng : Cabazitaxel is an anti-neoplastic used with the steroid medicine prednisone. Cabazitaxel is used to treat people with prostate cancer that has progressed despite treatment with docetaxel. Cabazitaxel is prepared by semi-synthesis with a precursor extracted from yew needles (10-deacetylbaccatin III). It was approved by the U.S. Food and Drug Administration (FDA) on June 17, 2010. Cabazitaxel is a microtubule inhibitor. Cabazitaxel binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the interference of mitotic and interphase cellular functions. The cell is then unable to progress further into the cell cycle, being stalled at metaphase, thus triggering apoptosis of the cancer cell.

Dược Động Học :

▧ Absorption :
After an intravenous dose of cabazitaxel 25 mg/m2 every three weeks to a population of 170 patients with solid tumors, the mean Cmax in patients with metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end of the one-hour infusion (Tmax). The mean AUC in patients with metastatic prostate cancer was 991 ng.h/mL (CV 34%). Administration with prednisone or prednisolone do not effect the pharmacokinetic profile of cabazitaxel.
▧ Volume of Distribution :
The volume of distribution (Vss) was 4,864 L (2,643 L/m2 for a patient with a median BSA of 1.84 m2) at steady state. Compared to other taxanes, penetrates the CNS to a greater extent.
▧ Protein binding :
Cabazitaxel is mainly bound to human serum albumin (82%) and lipoproteins (88% for HDL, 70% for LDL, and 56% for VLDL).
▧ Metabolism :
Cabazitaxel is extensively metabolized in the liver (>95%), mainly by the CYP3A4/5 isoenzyme (80% to 90%), and to a lesser extent by CYP2C8 which results in 20 different metabolites. Two of these metabolites are active demethylated derivatives of cabaxitaxel and referred to as RPR112698 and RPR123142 respectively. Docetaxel is another metabolite of cabazitaxel. Cabazitaxel is the main circulating moiety in human plasma.
▧ Route of Elimination :
After a one-hour intravenous infusion [14C]-cabazitaxel 25 mg/m2, approximately 80% of the administered dose was eliminated within 2 weeks. Cabazitaxel is mainly excreted in the feces as numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and metabolites account for 3.7% of the dose (2.3% as unchanged drug in urine).
▧ Half Life :
Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic model with α-, β-, and γ- half-lives of 4 minutes, 2 hours, and 95 hours, respectively.
▧ Clearance :
Cabazitaxel has a plasma clearance of 48.5 L/h (CV 39%; 26.4 L/h/m2 for a patient with a median BSA of 1.84 m2) in patients with metastatic prostate cancer.

Độc Tính : Cabazitaxel may cause serious side effects including neutropenia, hypersensitivity reactions, gastrointestinal symptoms, and renal failure. Anticipated complications of overdose include exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders. Cabazitaxel penetrates the blood-brain barrier. LD50, rat = 500 mg/kg

Chỉ Định : For treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.

Tương Tác Thuốc :

Atazanavir Concomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
Carbamazepine Concomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
Cisplatin Platinum derivatives such as cisplatin may enhance the myelosuppressive effect of taxane derivatives such as cabazitaxel. Administer taxane derivative before platinum derivative when given as sequential infusions to limit toxicity.Administer paclitaxel before cisplatin, when given as sequential infusions, to limit toxicity. Problems associated with other taxane/platinum combinations are possible, although unsubstantiated. Administering the taxane derivative before the platinum derivative seems prudent.
Clarithromycin Concomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
Indinavir Concomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
Itraconazole Concomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
Ketoconazole Concomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
Nefazodone Concomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
Nelfinavir Concomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
Phenobarbital Concomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
Phenytoin Concomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
Rifabutin Concomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
Rifampicin Concomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
Rifapentine Concomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
Ritonavir Concomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
Saquinavir Concomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
St. John's Wort Concomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
Telithromycin Concomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
Voriconazole Concomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.

Liều Lượng & Cách Dùng : Injection - Intravenous - 60mg/1.5mL

Dữ Kiện Thương Mại

Nhà Sản Xuất

Công ty : Sanofi-Aventis US

Sản phẩm biệt dược : Jevtana

Tài Liệu Tham Khảo Thêm

drugbank

http://www.drugbank.ca/drugs/DB06772

PubChem Compound

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=9854073

PubChem Substance

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=99443289

KEGG Drug

http://www.genome.jp/dbget-bin/www_bget?drug:D09755

ChemSpider

http://www.chemspider.com/Chemical-Structure.8029779.html

National Drug Code Directory

http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0024-5824-11

PharmGKB

http://www.pharmgkb.org/drug/PA165958401

Wikipedia

http://en.wikipedia.org/wiki/Cabazitaxel

RxList

http://www.rxlist.com/jevtana-drug.htm

Drugs.com

http://www.drugs.com/pro/jevtana.html

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