Mini-Reviews in Medicinal Chemistry, 2013, 13, 000-000
`
`Send Orders of Reprints at reprints@benthamscience.net
`1
`
` Cabazitaxel: A Novel Drug for Hormone-Refractory Prostate Cancer
`
`Manav Malhotra1, Richa Dhingra1, Tina Sharma1, Aakash Deep2,*, Balasubramanian Narasimhan2,
`Priyanka Phogat3 and Prabodh Chander Sharma4
`
`1Department of Pharmaceutical Chemistry, I.S.F. College of Pharmacy, Ferozpur Road, Moga 142021, India;
`2Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak-124001, India; 3Department of
`pharmaceutical Sciences, Hindu College of Pharmacy, Sonepat-131001, India; 4Institute of Pharmaceutical Sciences,
`Kurukshetra University, Kurukshetra-136118, India
`
`Abstract: Cabazitaxel has recently been approved by FDA for the treatment of docetaxel resistant hormone-refractory
`prostate cancer. It has been developed by Sanofi-Aventis under the trade name of Jevtana. It is given in combination with
`prednisone/prednisolone and has passed the clinical trial over well-known drug mitoxantrone. This drug is a microtubule
`depolymerization inhibitor, which can penetrate blood brain barrier (BBB). The FDA granted fast track designation to this
`drug in November 2009 and thereafter, new drug application submission was done in March 2010. Priority review to this
`drug was granted in April 2010 and finally in July 2010 it was approved by FDA. It is available in the form of injection in
`the dose of 60 mg/1.5 mL, which should be diluted prior to its use by the diluents supplied along with the injection. It is a
`second-line drug and has proven to be effective in patients experiencing docetaxel based treatment failure.
`
`Keywords: Prostate cancer, Jevtana, Sanofi-aventis, Taxanes, Cabazitaxel, XRP-6258.
`
`INTRODUCTION
`
` Cabazitaxel is a recently introduced drug as a second line
`treatment after docetaxel failure for metastatic castrate
`resistant prostate cancer (MCRPC) in men. It has recently
`been approved by US-FDA in June 2010 as a second line
`drug for treatment of hormone-refractory prostate cancer. It
`was developed by Sanofi-Aventis and was named as Jevtana,
`previously called as XRP-6258 [1]. The development of
`cabazitaxel is being considered as a major success in second
`line chemotherapy for advance prostate cancer because it
`shows more survivals as compared to docetaxel treated
`patients for the same cancer type [2]. It has gone through 3
`TROPIC phase 3 trial on 755 patients suffering from
`advanced prostate cancer, all of them had earlier been treated
`with docetaxel earlier and the medium survival was reported
`15.1 months. It is generally used in combination with
`Prednisone/ Prednisolone [3]. Cabazitaxel acts by binding to
`beta-tubulin, promotes its assembly to microtubules, and
`inhibits its disassembly which leads to stabilization of
`microtubules and in this way inhibits mitotic and interphase
`cellular functions [4]. It causes microtubule depolymerization
`inhibition and inhibits cell division, which leads to cell cycle
`arrest in G2/M phase and inhibition of tumor cell proliferation.
`In contrast to other taxane compounds, cabazitaxel can
`penetrate blood brain barrier (BBB), is a poor substrate
`for the membrane-associated, multidrug resistance (MDR),
`P-glycoprotein (P-gp) efflux pump, and is believed to be
`useful for treating multidrug-resistant tumors [5]. Cabazitaxel is
`an antineoplastic agent belonging to the taxane class which is
`
`
`the Department of
`this author at
`to
`*Address correspondence
`Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak-124001,
`Haryana, India; Mobile: +919896096727; E-mail: aakashdeep82@gmail.com
`
`prepared by semi-synthetic methods with a precursor
`extracted from yew needles [6]. Prostate cancer ranks third
`worldwide in cancer incidences and sixth in cancer mortality
`in men. In U.S., it is reported to be the second most common
`cause of death among men after lung cancer. The 2009
`statistics shows that 1,92,000 new cases were anticipated in
`U.S., about 15,000-20,000 American men had
`to be
`successfully treated with taxotere and 27,000 were expected
`to die from this disease each year [7]. The term metastatic
`prostate cancer indicates that the cancer has spread or
`metastasized to lymph nodes or other parts of the body
`especially to bones, in which 10-20% cases are diagnosed
`when
`the cancer has already metastasized. Castration
`resistant/prostate cancer means that cancer is continuously
`growing despite the suppression of male hormone which acts
`as a fuel for the prostate cancer cells. More than 80 percent
`cases are diagnosed when the cancer is in prostate or in
`surrounding organs [8]. Cabazitaxel is a novel taxane
`derivative and is the first to show a survival benefit to
`patients with metastatic hormone refractory prostate cancer
`after failure of docetaxel (taxotere) based therapy. Cabazitaxel
`significantly improves survival in men with prostate cancer
`when compared
`to mitoxantrone, who have received
`docetaxel prior to it [9]. The dose of cabazitaxel which is
`recommended to be used is 25 mg/m2 but at this dose the
`patients experienced several side effects some of them being
`even fatal. However when its therapeutic dose was reduced
`to 20mg/m2, the incidences of side effects were also reported
`to be reduced in some patients [10]. The death rate was
`observed to be decreased upto 30% in patients administered
`cabazitaxel when compared to mitoxantrone containing
`regimen. It is extensively metabolized extensively in liver and
`gives seven metabolites out of which three are biologically
`
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`2 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 2
`
`Malhotra et al.
`
`active which are formed by o-demethylation. Cabazitaxel
`and its metabolites are extensively excreted in urine and
`faeces [11].
`
`CHEMISTRY
`
` The chemical name of cabazitaxel (Fig. 1) is (2(cid:1),5(cid:2),7(cid:2),
`10(cid:2),13(cid:1))-4-acetoxy-13-({(2R,3S)-3-[(tertbutoxycarbonyl)
`amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-
`dimethoxy-9-oxo-5,20-epoxytax-11-en-2-yl-benzoate-
`propan-2-one [12]. Its molecular formula is C45H57NO14.C3H6O
`and a molecular weight of 894.01. It is white to off-white
`powder having lipophilic nature and is practically insoluble
`in water but soluble in alcohol [13]. It is synthesized from
`natural
`taxoid 10-deacetylbaccatin-III, having potential
`antineoplastic activity [14].
`
`
`
`O
`
`O
`
`O
`
`O
`
`O
`
`NH
`
`O
`
`O
`
`OH
`
`HO
`
`O
`
`O
`
`O
`
`O
`
`of cabazitaxel as it is mainly metabolized by CYP3A
`[18].Cabazitaxel is always administered along with 10 mg of
`prednisone/prednisolone which shows no effect on its
`pharmacokinetics. At higher doses, cabazitaxel inhibits the
`transport of MRPs, P-gp and BRCP in clinical trials but does
`no exhibit any effect preclinically [19].
`
`MECHANISM OF ACTION
`
` Cabazitaxel acts by inhibiting microtubules by preventing
`its disassembly and by promoting its assembly, which leads
`to its stabilization resulting in inhibition of mitotic and
`interphase cellular functions [20]. Microtubule performs
`many cellular functions like cell shape maintenance, vesicles
`and mitochondria
`transportation
`throughout cell, cell
`signaling, cell division and mitosis [21]. The diagrammatic
`representation of mechanism of action of cabazitaxel is
`shown in (Fig. 2). All anticancer agents act by different
`mechanisms of action; some act at vinca binding site like
`vincristine, vinblastine etc, [22]; some act at colchicine
`binding site like combretastatin, podophyllotoxins etc and
`some act at taxane binding site like paclitaxel, cabazitaxel
`etc [23]. The combined mechanism of action of cabazitaxel
`is shown in (Fig. 3).
`
`O
`
`
`
`
`
`
`Fig. (1). Chemical structure of cabazitaxel.
`
`
`PHARMACODYNAMIC ASPECT
`
` Cabazitaxel demonstrated antitumor activity against
`advanced human tumors xenografted in mice. The drug has
`been observed to be active in docetaxel-sensitive tumors. In
`addition, cabazitaxel demonstrated activity in tumor models
`insensitive to chemotherapy including docetaxel [15].
`
`PHARMACOKINETICS ASPECTS
`
` Cabazitaxel is primarily metabolized by CYP3A4/5
`primarily and also by CYP2C8 up to lesser extent. It leads to
`multiple metabolites out of which three are active formed
`from O-demethylation. The drug is 89-92% protein bound
`and its volume of distribution is 4,864L [16]. Cmax of
`cabazitaxel is 226 ng/mL and is achived up to end of 1-h
`infusion. Half-life of cabazitaxel is 4 min for alpha phase, 2
`h for beta phase and 95 h for gamma phase. Clearance of this
`compound is 48.5 L/h and is excreted approximately 4% in
`urine out of which 2.3% is unchanged drug and 76% is
`excreted in feaces [17]. Strong CYP3A inducers like
`carbamazepine, phenobarbitone, phenytoin,
`rifabutin,
`rifampin, rifapentin and St john’s wart [17] or inhibitors like
`atazanavir,
`clarithromycin,
`indinavir,
`ketoconazole,
`itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir,
`telithromycin and voriconazole affect the pharmacokinetics
`
`
`Fig. (2). Structure and function of microtubules and mechanism of
`action of tubulin binding agents.
`
`
`
`
`CLINICAL STUDIES
`
` Cabazitaxel TROPIC trial was conducted in 146 trial
`sites in 26 countries. In this phase 3 trial, 755 metastatic
`hormone refractory prostate cancer patients, previously
`treated with docetaxel containing treatment regimen, were
`administered cabazitaxel in combination with prednisone
`[24]. Results from this trial demonstrated a statistically
`significant 30% [HR=0.70 (95% CI: 0.59-0.83); P<0.0001]
`reduction in risk of death from (Mcrpc) among patients
`taking the drug in combination with prednisone compared
`with an active chemotherapy regimen consisting of a
`
`

`
`Cabazitaxel: A Novel Drug for Hormone-Refractory Prostate Cancer
`
`Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 2 3
`
`
`Fig. (3). Microtubule destabilizers and stabilizers and their binding sites on tubulin.
`
`
`
`
`[25].
`standard dose of mitoxantrone and prednisone
`Investigator-assessed
`that
`tumor
`response
`rates using
`response evaluation criteria in solid tumors (RECIST) were
`14.4% and 4.4% for cabazitaxel-treated and mitoxantrone-
`treated patients
`respectively, p=0.0005. No complete
`responses were observed on either arm [26]. The primary
`endpoint was overall survival. Secondary endpoints included
`progression-free survival,
`tumor
`response
`rate,
`tumor
`progression, prostate-specific antigen (PSA) response, PSA
`progression, pain response, and pain progression. Disease
`progression in this trial was defined as tumor progression,
`PSA progression or pain progression [27]. Other secondary
`endpoints were overall safety of cabazitaxel in combination
`with prednisone, the pharmacokinetics of cabazitaxel and its
`metabolite in this patient population, and the effect of
`prednisone on the pharmacokinetics of cabazitaxel [27].
`Patients were randomly assigned to receive cabazitaxel plus
`prednisone/ prednisolone or mitoxantrone plus prednisone/
`prednisolone (378 and 377 patients, respectively). Patients
`were to receive either regimen for up to a maximum of 10
`cycles [28]. The in vivo parameters of cabazitaxel have been
`shown in Table 1.
`
`FDA APPROVAL AND MARKET AUTHORIZATION
`
` The FDA approval of cabazitaxel was based on clinical
`trials carried out either alone or in comparison with
`docetaxel or mitoxantrone with prednisone/prednisolone. On
`17th June 2010 [29], FDA approved this drug because of its
`better responses and better survival rates for the patients
`suffering from hormone refractory metastatic prostate cancer.
`The approval was granted on the results of randomized open
`label, international trial on 755 patients with mHRPC, who
`had been already treated with docetaxel therapy. Patients
`were treated until death, disease progression, unacceptable
`
`toxicity, or completion of 10 cycles of therapy [30]. It was
`also found to be effective for those patients who have
`metastatic castration
`resistant prostate cancer.
`It
`is
`considered as second
`line drug after mitoxantrone/
`prednisone combination and also in cases of docetaxel
`failure regimen [31]. This study has been registered at
`ClinicalTrials.gov,NCT00417079. Results demonstrate that
`it actually increases the survival rates of patients with
`advanced prostate cancer. It acts at tubulin binding sites in
`microtubules like other taxanes of its family. It inhibits the
`mitosis and interphase of cell cycle, thus inhibiting the
`growth of cancer cells [32]. Jevtana is the trade name under
`which this drug is being marketed. It is synthesized by
`Sanofi-aventis company and several clinical tests have been
`conducted to confer this drug as the second-line drug in
`patients with mCRPC who were resistant to docetaxel
`regimen therapy [33]. It has been shown by the manufacturers
`that cabazitaxel along with prednisone/prednisolone decrease
`the death rate by 30 percent in mCRPC patients [34]. This
`drug is synthesized for the castration resistant prostate cancer
`patients and may prove to be the remarkable invention for
`the betterment of mankind. Though it reports some side
`effects, but these can be minimized by decreasing its dose or
`by increasing its dosage interval [35].
`
`DOSAGE
`
` Cabazitaxel is administered in the form of intravenous
`injection. Before administering cabazitaxel a 30 minute prior
`medication of IV antihistaminic (dexchlorpheniramine 5mg,
`diphenhydramine 25mg, or equivalent), an IV corticosteroid
`(dexamethasone 8mg or equivalent) and an IV H2 antagonist
`(ranitidine 50 mg or equivalent) drug should be provided in
`order to avoid hypersensitivity reaction [36]. The cabazetaxel
`should be given 25mg/m2 intravenously over 1 h every 3
`
`

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`4 Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 2
`
`Malhotra et al.
`
`Table 1.
`
`In Vivo Parameters of Cabazitaxel [26-28]
`
`S. No
`
`Properties
`
`Cabazitaxel
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Vd
`
`Cl
`
`T (cid:1)
`
`Protien binding
`
`Excretion
`
`Dosage
`
`Trade Name
`
`4,864
`
`48.5L
`
`4 min((cid:2) phase), 2h((cid:3) phase), 95h((cid:4) phase)
`
`89%-92%
`
`4% in urine & 76% in feces
`
`60mg/1.5ml IV
`
`Jevtana (sanofi-aventis)
`
`
`
`weeks in combination with 10 mg oral prednisone daily. The
`treatment should be delayed if the patient has less than 1500
`cells/mm3 neutrophil counts otherwise decrease the dose of
`cabazitaxel should be decreased 20 mg/m2, granulocyte
`colony-stimulating factor (G-CSF) can be used for secondary
`prophylaxis and in addition antiemetic treatment is also
`recommended [37]. Based on calculation of the body surface
`area (BSA) the dose of cabazitaxel can be calculated which
`is administered every three weeks as a one-hour intravenous
`infusion in combination with oral prednisone 10 mg
`administered daily throughout the treatment. Premedication
`prior to treatment is recommended. Under the supervision of
`a qualified physician drug should be administered. Adequate
`diagnostic and treatment facilities should be readily available
`for the appropriate management of complications. Jevtana
`Injection single-use vial requires two dilutions prior to
`administration. PVC infusion containers and polyurethane
`infusions sets
`for preparation and administration of
`cabazitaxel infusion solution should not be used [38].
`
`ADVERSE EFFECT
`
` The side effects which are being experienced with this
`drug during clinical trials are arrhythmia, hypotension,
`peripheral neuropathy, dysgeusia, abdominal pain, anorexia,
`dyspepsia, hematuria, urinary tract infection, dysuria,
`leucopenia, neutropenia, thrombocytopenia, arthralgia,
`muscle spasms, dyspnea, cough, pyrexia, alopecia and mucosal
`inflammation. The incidences stated for the following
`adverse reactions were reported with cabazitaxel 25 mg/m2
`in combination with prednisone 10 mg daily [39]. GI effects
`include nausea, vomiting, and severe diarrhoea. In some
`clinical trials, death related to diarrhoea and electrolyte
`imbalance has been reported. Patients should be treated with
`rehydration and antidiarrhoeal or antiemetic medications as
`needed. Treatment should be delayed or dosage can be
`reduced in case of any severe emergency like severe
`diarrhoea. Renal effects include renal failure with fatal
`outcomes as well. These cases occurred in association with
`dehydration, obstructive uropathy, or sepsis. Etiology of
`deaths due to renal failure is still not clear. Appropriate
`measures should be taken to identify renal failure and should
`be treated immediately [40].
`
`
`
`PRECAUTIONS
`
` This drug should not be used in some special patients
`having neutrophil count less than 1500/cell and in patients
`having severe hypersentivity reactions. It is not suitable to be
`administered along with CYP23A inhibitors and inducers as
`both affect its bioavailability and vice-versa. It should not be
`prescribed to pregnant women and lactating mothers. Other
`conditions where precautionary measures are required are as
`follows:
`
`HYPERSENSITIVITY
`
`the patient experiences hypersensitive reactions
`If
`
`(hypotension, bronchospasm, and/or generalized
`rash/
`erythma) on administration of cabazitaxel, the dose must be
`reduced to 20 mg/m2 from 25 mg/m2 and co-administration
`of antihistaminic drugs should be done or in severe cases the
`dosage should be immediately stopped or G-CSF may also
`be administered [41].
`
`NEUTROPENIA
`
` Cabazitaxel should carefully be administered to patients
`with neutrophil counts less than 1500 cells/mm3. Frequent
`blood cell counts should be performed on its administration.
`Neutropenic deaths have been usually reported during the
`treatment [41]. The death rate was 2% in mitoxantrone
`whereas 5% in cabazitaxel primarily due to infection.
`
`GRANULOCYTE COLONY-STIMULATING FACTOR
`
` G-CSF may be administered to reduce the risks of
`complications like neutropenia. Primary prophylaxis in
`patients with high-risk clinical features can be done [42].
`Therapeutic use of G-CSF and secondary prophylaxis in all
`patients should be done in order to decrease the risk of
`neutropenia complications.
`
`COMPARISON
`MITOXANTRONE
`
`OF
`
`CABAZITAXEL WITH
`
` When cabazitaxel was administered with prednisone the
`death rate during the therapy was noted as 61% as compared
`to 74% when treatment was carried out with mitoxantrone/
`prednisone combination and the median survival was 15.1
`months with cabazitaxel/prednisone combination and 12.7
`months with mitoxantrone/prednisone combination. Moreover,
`
`

`
`Cabazitaxel: A Novel Drug for Hormone-Refractory Prostate Cancer
`
`Mini-Reviews in Medicinal Chemistry, 2013, Vol. 13, No. 2 5
`
`this drug is efficient to be used in case of Paclitaxel Resistant
`Patient [43, 44].
`
`CONCLUSION
`
`Significant pharmacological interventions, mechanism of
`
`action, available pharmacokinetic and pharmacodynamic
`aspects along with clinical data of this recently introduced
`drug have been described in the present paper. Cabazitaxel, a
`second line drug for metastatic castration resistant prostate
`cancer, has improved quality of life in patients with
`progressive disease after docetaxel based treatment. It has
`resulted in an improved median survival as well as 30%
`reduction in the death rates as compared with mitoxantrone.
`It was further emphasized that significant scientific and
`technological advancements in pharmacological aspects,
`medicinal chemistry, and analytical techniques are still
`insistently required to optimally harness the therapeutic
`benefits of this potent drug.
`
`CONFLICT OF INTEREST
`
` The authors confirm that this article content has no
`conflicts of interest.
`
`ACKNOWLEDGEMENTS
`
` Declared none.
`
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`Received: July 20, 2011
`
`Revised: August 16, 2012
`
` Accepted: August 20, 2012
`
`
`
`DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The
`Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.
`
`PMID: 22950608