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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
Taxoid XRP6258Not AvailableNot Available
TXD258Not AvailableNot Available
XRP6258Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
JevtanaSanofi-Aventis US
Brand mixturesNot Available
CategoriesNot Available
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[11.3.1.0^{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
    DocetaxelDetails
    Cabazitaxel
      RPR112698Details
      Cabazitaxel
        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

        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

        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.

        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

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