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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
SynonymLanguageCode
CabazitaxelumNot AvailableNot Available
Taxoid XRP6258Not AvailableNot Available
TXD258Not AvailableNot Available
XRP6258Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
JevtanaSanofi-Aventis US
Brand mixturesNot Available
Categories
CAS number183133-96-2
WeightAverage: 835.9324
Monoisotopic: 835.377905537
Chemical FormulaC45H57NO14
InChI KeyBMQGVNUXMIRLCK-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[11.3.1.0^{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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassPrenol Lipids
SubclassDiterpenes
Direct parentTaxanes and 11(15->1)Abeotaxanes
Alternative parentsGermacrane Sesquiterpenes; Phenylpyruvic Acid Derivatives; Phenylpropylamines; Benzoic Acid Esters; Tricarboxylic Acids and Derivatives; Benzylethers; Benzoyl Derivatives; Tertiary Alcohols; Secondary Alcohols; Ketones; Oxetanes; Carbamic Acids and Derivatives; Carboxylic Acid Esters; Cyclic Alcohols and Derivatives; Dialkyl Ethers; Polyamines; Enolates; Aldehydes
Substituentsgermacrane sesquiterpene; phenylpyruvate; benzoate ester; phenylpropylamine; benzylether; benzoic acid or derivative; tricarboxylic acid derivative; benzoyl; benzene; cyclic alcohol; tertiary alcohol; carboxylic acid ester; carbamic acid derivative; oxetane; ketone; secondary alcohol; ether; dialkyl ether; enolate; carboxylic acid derivative; polyamine; alcohol; carbonyl group; amine; organonitrogen compound; aldehyde
Classification descriptionThis compound belongs to the taxanes and 11(15->1)abeotaxanes. These are diterpenes whose structure is based on the taxane or 11(15->1)abeaotaxane skeleton, which is characterized by a 6-8-6 tricyclic ring system.
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
Property Value Probability
Human Intestinal Absorption + 0.9535
Blood Brain Barrier - 0.9825
Caco-2 permeable - 0.7945
P-glycoprotein substrate Substrate 0.8287
P-glycoprotein inhibitor I Inhibitor 0.6646
P-glycoprotein inhibitor II Inhibitor 0.5887
Renal organic cation transporter Non-inhibitor 0.933
CYP450 2C9 substrate Non-substrate 0.8236
CYP450 2D6 substrate Non-substrate 0.882
CYP450 3A4 substrate Substrate 0.7256
CYP450 1A2 substrate Non-inhibitor 0.8197
CYP450 2C9 substrate Non-inhibitor 0.8654
CYP450 2D6 substrate Non-inhibitor 0.8935
CYP450 2C19 substrate Non-inhibitor 0.8429
CYP450 3A4 substrate Non-inhibitor 0.6339
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9068
Ames test Non AMES toxic 0.8028
Carcinogenicity Non-carcinogens 0.9264
Biodegradation Not ready biodegradable 0.9926
Rat acute toxicity 2.6378 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9907
hERG inhibition (predictor II) Non-inhibitor 0.7906
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
InjectionIntravenous60mg/1.5mL
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 solubility4.13e-03 g/lALOGPS
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 area202.45ChemAxon
rotatable bond count15ChemAxon
refractivity213.4ChemAxon
polarizability86.39ChemAxon
number of rings6ChemAxon
bioavailability0ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

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

US20120065255
General Reference
  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
ResourceLink
KEGG DrugD09755
PubChem Compound9854073
PubChem Substance99443289
ChemSpider8029779
ChEBI63584
ChEMBLCHEMBL1201748
PharmGKBPA165958401
RxListhttp://www.rxlist.com/jevtana-drug.htm
Drugs.comhttp://www.drugs.com/pro/jevtana.html
WikipediaCabazitaxel
ATC CodesL01CD04
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelshow(383 KB)
MSDSshow(99.2 KB)
Interactions
Drug Interactions
Drug
AtazanavirConcomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
CarbamazepineConcomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
CisplatinPlatinum 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.
ClarithromycinConcomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
IndinavirConcomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
ItraconazoleConcomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
KetoconazoleConcomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
NefazodoneConcomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
NelfinavirConcomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
PhenobarbitalConcomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
PhenytoinConcomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
RifabutinConcomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
RifampicinConcomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
RifapentineConcomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
RitonavirConcomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
SaquinavirConcomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
St. John's WortConcomitant therapy with a strong CYP3A inducer may decrease concentrations of cabazitaxel. Avoid concomitant therapy.
TelithromycinConcomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
VoriconazoleConcomitant therapy with a strong CYP3A4 inhibitor may increase concentrations of cabazitaxel. Avoid concomitant therapy.
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