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Identification
NameCabazitaxel
Accession NumberDB06772
TypeSmall Molecule
GroupsApproved
Description

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.

Structure
Thumb
Synonyms
Cabazitaxelum
Taxoid XRP6258
TXD258
XRP6258
External Identifiers
  • RPR-116258A
  • RPR116258
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
JevtanakitSanofi Aventis U.S. Llc2010-06-17Not applicableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Jevtanasolution40 mgintravenousSanofi Aventis Canada Inc2011-08-23Not applicableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number183133-96-2
WeightAverage: 835.9324
Monoisotopic: 835.377905537
Chemical FormulaC45H57NO14
InChI KeyInChIKey=BMQGVNUXMIRLCK-OAGWZNDDSA-N
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
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
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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as taxanes and derivatives. These are diterpenoids with a structure based either on the taxane skeleton, or a derivative thereof. In term of phytochemistry, several derivatives of the taxane skeleton exist
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassPrenol lipids
Sub ClassDiterpenoids
Direct ParentTaxanes and derivatives
Alternative Parents
Substituents
  • Taxane diterpenoid
  • Phenylpropylamine
  • Benzoate ester
  • Tricarboxylic acid or derivatives
  • Benzylether
  • Benzoic acid or derivatives
  • Benzoyl
  • Fatty acid ester
  • Fatty acyl
  • Benzenoid
  • Monosaccharide
  • Monocyclic benzene moiety
  • Acetate salt
  • Tertiary alcohol
  • Cyclic alcohol
  • Secondary alcohol
  • Oxetane
  • Ketone
  • Carboxylic acid ester
  • Oxacycle
  • Organoheterocyclic compound
  • Ether
  • Dialkyl ether
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.
PharmacodynamicsCabaitaxel has anti-tumour properties and is effective against docetaxel-sensitive and -insensitive tumours.
Mechanism of actionCabazitaxel 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.
AbsorptionAfter 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 bindingCabazitaxel 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.

SubstrateEnzymesProduct
Cabazitaxel
Not Available
DocetaxelDetails
Cabazitaxel
Not Available
RPR112698Details
Cabazitaxel
Not Available
RPR123142Details
Route of eliminationAfter 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 lifeFollowing 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.

ToxicityCabazitaxel 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
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9535
Blood Brain Barrier-0.9825
Caco-2 permeable-0.7945
P-glycoprotein substrateSubstrate0.8287
P-glycoprotein inhibitor IInhibitor0.6646
P-glycoprotein inhibitor IIInhibitor0.5887
Renal organic cation transporterNon-inhibitor0.933
CYP450 2C9 substrateNon-substrate0.8236
CYP450 2D6 substrateNon-substrate0.882
CYP450 3A4 substrateSubstrate0.7256
CYP450 1A2 substrateNon-inhibitor0.8197
CYP450 2C9 inhibitorNon-inhibitor0.8654
CYP450 2D6 inhibitorNon-inhibitor0.8935
CYP450 2C19 inhibitorNon-inhibitor0.8429
CYP450 3A4 inhibitorNon-inhibitor0.6339
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9068
Ames testNon AMES toxic0.8028
CarcinogenicityNon-carcinogens0.9264
BiodegradationNot ready biodegradable0.9926
Rat acute toxicity2.6378 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9907
hERG inhibition (predictor II)Non-inhibitor0.7906
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Kit
Solutionintravenous40 mg
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States54380722010-06-172013-11-22
United States56985822010-06-172012-07-03
United States58471702010-06-172016-03-26
United States63316352010-06-172016-03-26
United States63727802010-06-172016-03-26
United States63879462010-06-172016-03-26
United States72419072010-06-172025-12-10
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00413 mg/mLALOGPS
logP3.69ALOGPS
logP4.2ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)11.97ChemAxon
pKa (Strongest Basic)-3.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area202.45 Å2ChemAxon
Rotatable Bond Count15ChemAxon
Refractivity213.4 m3·mol-1ChemAxon
Polarizability86.39 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Nagesh Palepu, “CABAZITAXEL FORMULATIONS AND METHODS OF PREPARING THEREOF.” U.S. Patent US20120065255, issued March 15, 2012.

US20120065255
General References
  1. Galsky MD, Dritselis A, Kirkpatrick P, Oh WK: Cabazitaxel. Nat Rev Drug Discov. 2010 Sep;9(9):677-8. Pubmed
  2. Kort A, Hillebrand MJ, Cirkel GA, Voest EE, Schinkel AH, Rosing H, Schellens JH, Beijnen JH: Quantification of cabazitaxel, its metabolite docetaxel and the determination of the demethylated metabolites RPR112698 and RPR123142 as docetaxel equivalents in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2013 Apr 15;925:117-23. doi: 10.1016/j.jchromb.2013.02.034. Epub 2013 Mar 5. Pubmed
  3. Nightingale G, Ryu J: Cabazitaxel (jevtana): a novel agent for metastatic castration-resistant prostate cancer. P T. 2012 Aug;37(8):440-8. Pubmed
External Links
ATC CodesL01CD04
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (383 KB)
MSDSDownload (99.2 KB)
Interactions
Drug Interactions
Drug
AprepitantThe serum concentration of Cabazitaxel can be increased when it is combined with Aprepitant.
AtazanavirThe serum concentration of Cabazitaxel can be increased when it is combined with Atazanavir.
BexaroteneThe serum concentration of Cabazitaxel can be decreased when it is combined with Bexarotene.
BoceprevirThe serum concentration of Cabazitaxel can be increased when it is combined with Boceprevir.
BosentanThe serum concentration of Cabazitaxel can be decreased when it is combined with Bosentan.
CeritinibThe serum concentration of Cabazitaxel can be increased when it is combined with Ceritinib.
CisplatinCisplatin may increase the myelosuppressive activities of Cabazitaxel.
ClarithromycinThe serum concentration of Cabazitaxel can be increased when it is combined with Clarithromycin.
ClozapineThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Clozapine.
CobicistatThe serum concentration of Cabazitaxel can be increased when it is combined with Cobicistat.
ConivaptanThe serum concentration of Cabazitaxel can be increased when it is combined with Conivaptan.
DabrafenibThe serum concentration of Cabazitaxel can be decreased when it is combined with Dabrafenib.
DarunavirThe serum concentration of Cabazitaxel can be increased when it is combined with Darunavir.
DasatinibThe serum concentration of Cabazitaxel can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of Cabazitaxel can be decreased when it is combined with Deferasirox.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Cabazitaxel.
DoxorubicinThe metabolism of Doxorubicin can be decreased when combined with Cabazitaxel.
FluconazoleThe metabolism of Cabazitaxel can be decreased when combined with Fluconazole.
FosaprepitantThe serum concentration of Cabazitaxel can be increased when it is combined with Fosaprepitant.
Fusidic AcidThe serum concentration of Cabazitaxel can be increased when it is combined with Fusidic Acid.
IdelalisibThe serum concentration of Cabazitaxel can be increased when it is combined with Idelalisib.
IndinavirThe serum concentration of Cabazitaxel can be increased when it is combined with Indinavir.
ItraconazoleThe serum concentration of Cabazitaxel can be increased when it is combined with Itraconazole.
IvacaftorThe serum concentration of Cabazitaxel can be increased when it is combined with Ivacaftor.
KetoconazoleThe serum concentration of Cabazitaxel can be increased when it is combined with Ketoconazole.
LeflunomideThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Leflunomide.
LuliconazoleThe serum concentration of Cabazitaxel can be increased when it is combined with Luliconazole.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Cabazitaxel.
MifepristoneThe serum concentration of Cabazitaxel can be increased when it is combined with Mifepristone.
MitotaneThe serum concentration of Cabazitaxel can be decreased when it is combined with Mitotane.
MitoxantroneThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Mitoxantrone.
NatalizumabThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Natalizumab.
NefazodoneThe serum concentration of Cabazitaxel can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Cabazitaxel can be increased when it is combined with Nelfinavir.
NetupitantThe serum concentration of Cabazitaxel can be increased when it is combined with Netupitant.
PalbociclibThe serum concentration of Cabazitaxel can be increased when it is combined with Palbociclib.
PhenytoinThe metabolism of Cabazitaxel can be increased when combined with Phenytoin.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Cabazitaxel.
PosaconazoleThe serum concentration of Cabazitaxel can be increased when it is combined with Posaconazole.
RitonavirThe serum concentration of Cabazitaxel can be increased when it is combined with Ritonavir.
RoflumilastRoflumilast may increase the immunosuppressive activities of Cabazitaxel.
SaquinavirThe serum concentration of Cabazitaxel can be increased when it is combined with Saquinavir.
SiltuximabThe serum concentration of Cabazitaxel can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Cabazitaxel can be increased when it is combined with Simeprevir.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Cabazitaxel.
St. John's WortThe serum concentration of Cabazitaxel can be decreased when it is combined with St. John's Wort.
StiripentolThe serum concentration of Cabazitaxel can be increased when it is combined with Stiripentol.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Cabazitaxel.
TelaprevirThe serum concentration of Cabazitaxel can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Cabazitaxel can be increased when it is combined with Telithromycin.
TocilizumabThe serum concentration of Cabazitaxel can be decreased when it is combined with Tocilizumab.
TofacitinibCabazitaxel may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Cabazitaxel.
VoriconazoleThe serum concentration of Cabazitaxel can be increased when it is combined with Voriconazole.
Food InteractionsNot Available

Targets

1. Tubulin alpha-4A chain

Kind: Protein

Organism: Human

Pharmacological action: yes

Actions: binder

Components

Name UniProt ID Details
Tubulin alpha-4A chain P68366 Details

References:

  1. DailyMed: JEVTANA

2. Tubulin beta-1 chain

Kind: Protein

Organism: Human

Pharmacological action: yes

Actions: binder

Components

Name UniProt ID Details
Tubulin beta-1 chain Q9H4B7 Details

References:

  1. DailyMed: JEVTANA

Enzymes

1. Cytochrome P450 3A4

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. DailyMed: JEVTANA
  2. Assessment Report for Jevtana (Cabazitaxel). European Medicines Agency, Committee for Medicinal Products for Human Use. 2011 Jan.

2. Cytochrome P450 3A5

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. DailyMed: JEVTANA
  2. Assessment Report for Jevtana (Cabazitaxel). European Medicines Agency, Committee for Medicinal Products for Human Use. 2011 Jan.

3. Cytochrome P450 2C8

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. DailyMed: JEVTANA
  2. Assessment Report for Jevtana (Cabazitaxel). European Medicines Agency, Committee for Medicinal Products for Human Use. 2011 Jan.

Transporters

1. Multidrug resistance protein 1

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. DailyMed: JEVTANA

2. ATP-binding cassette sub-family G member 2

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 2 Q9UNQ0 Details

References:

  1. DailyMed: JEVTANA

3. Solute carrier organic anion transporter family member 1B1

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1B1 Q9Y6L6 Details

References:

  1. DailyMed: JEVTANA

4. Solute carrier organic anion transporter family member 1B3

Kind: Protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1B3 Q9NPD5 Details

References:

  1. DailyMed: JEVTANA

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Drug created on September 14, 2010 10:21 / Updated on September 16, 2013 18:04