Cabazitaxel - Uses, Mechanism of Action, Precautions and Side Effects

Overview

Cabazitaxel is an antineoplastic and taxane drug used in chemotherapy, along with steroids, to treat men who have metastatic castration-resistant prostate cancer (a type of prostate cancer that cannot be treated by surgery or medicines that lower testosterone levels). It is mainly used in patients who have already been treated with other medicines and do not respond to that medicine like Docetaxel. The administration of Cabazitaxel causes disturbances in the growth of cancer cells, which get destroyed and eventually lead to the proliferation of the normal cell. Cabazitaxel falls in a class of medications called microtubule inhibitors and is a semi-synthetic drug derived from the natural taxoid 10-deacetylbaccatin III. In addition, the drug has antineoplastic potential. Cabazitaxel binds and stabilizes tubulin, inhibiting microtubule depolymerization and cell division, cell cycle arrest in the G2/M phase, and resulting in inhibition of the tumor cell proliferation.

Dosage

• Cabazitaxel is indicated with steroids for the treatment of prostate cancer. An initial dose of 25 mg over one hour as an intravenous infusion every three weeks in combination with Prednisone 10 mg orally daily throughout treatment is necessary.

Preparation

Cabazitaxel comes in a kit and requires preparation of the mixing or diluting of the drug before use. The drug is prepared as below:

• First Dilution - Mix a small amount of Cabazitaxel 60 mg/1.5 ml from the container. Avoid foaming during dilution; do not shake. The final concentration of Cabazitaxel will be 10 mg/mL.

• Second Dilution - Take the recommended dose from the first dilution and dilute in a 250 mL polyvinyl chloride-free container with either 0.9 % sodium chloride or 5 % dextrose solution. Cabazitaxel solution should be between 0.1 mg/mL and 0.26 mg/mL. If the dose is greater than 65 mg, use a larger volume of infusion solution so that the concentration of Cabazitaxel is at most 0.26 mg/mL, which is an ideal concentration of Cabazitaxel. Use this final solution within eight hours stored at room temperature or within 24 hours if refrigerated, including infusion time.

Dosages and Usage

1. Prostate Cancer - Cabazitaxel is indicated along with Prednisone for metastatic castration-resistant prostate cancer in patients previously treated with a Docetaxel-containing treatment. The recommended dose is 20 mg/m2 IV throughout the treatment.

2. Neutropenia - In prolonged grade 3 neutropenia, despite appropriate medication, including G-CSF, delay the treatment until the neutrophil count is above 1,500 cells/mm3, then reduce the dose by 1 level.

3. Diarrhea - In grade 3 diarrhea despite appropriate medication, fluid, and electrolyte replacement, delay the treatment and then reduce the dose by 1 level.

4. Peripheral Neuropathy - In grade 2, reduces the dose by 1 level, and in grade 3, discontinue the therapy.

5. Strong CYP3A4 Inhibitors - Avoid coadministration; if unavoidable, reduce the dose by 25 %.

6. Renal Impairment - In all the severities, dosage adjustment is not necessary. End-stage renal disease (CrCl <15 mL/min) requires continued monitoring.

7. Hepatic Impairment

• Mild: A 20 mg/m2 is given.

• Moderate: The dose is reduced to 15 mg/m2; based on tolerability.

• Severe: Contraindicated.

Use in Special Populations

• Renal Impairment - No formal trials have been conducted in patients with renal impairment. Population pharmacokinetic trials included patients with mild to moderate renal impairment. However, no major effects were seen on the pharmacokinetics of Cabazitaxel. No data are available on the use in patients with severe renal impairment or end-stage renal disease.

• Hepatic Impairment - No formal trials have been conducted in patients with hepatic impairment. The liver extensively metabolizes Cabazitaxel. However, hepatic impairment will likely increase Cabazitaxel concentrations.

How Cabazitaxel Works?

Cancerous disorders lead to uncontrolled cell division. Normal cells stop proliferating when they come into contact with similar cells; this mechanism is known as contact inhibition, and cancerous cells lose this ability to control proliferation and cell division.

Chemotherapy kills cancer cells and can potentially stop the process of cell proliferation. If the cells fail to divide, they die. The use of chemotherapy damages the RNA or DNA of the cells. Chemotherapy leads to shrinkage of the tumor.

Chemotherapy is the most effective treatment and kills cells rapidly. However, chemotherapy fails to differentiate cancerous cells from normal ones. The normal and healthy cells are most commonly affected by chemotherapy. In addition, it affects the blood cells, the cells in the mouth, stomach, bowel, and hair growth, causing mouth sores, nausea, vomiting, and diarrhea.

Warning and Precautions

The administration of Cabazitaxel comes with some warnings and recommendations. Also, there are some precautions to avoid unfortunate circumstances. The followings are the warnings and precautions about Cabazitaxel:

1. Hypersensitivity Reactions - Patients undergoing the treatment should be pre-medicated before initiating the infusion of Cabazitaxel. Patients should be monitored closely for hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions can be observed in the first few minutes of the initial infusion of Cabazitaxel. Thus, facilities and equipment for treating low blood pressure and breathlessness should be available. Severe hypersensitivity reactions need supportive treatment. Cabazitaxel should be discontinued in patients with hypersensitivity reactions.

2. Bone Marrow Suppression - Cabazitaxel used in chemotherapy can result in bone marrow suppression, causing a lack of normal blood cells produced in the bone marrow by the hematopoietic stem cells.

3. Risk of Neutropenia - Patients treated with Cabazitaxel may receive prophylactic G-CSF, per American Society of Clinical Oncology (ASCO) guidelines and current institutional guidelines, to reduce the risk or manage neutropenia complications. Low white blood cell count is the most common adverse reaction of Cabazitaxel. Monitoring of complete blood counts is essential weekly during cycle one and before each treatment cycle is important.

4. Gastrointestinal Disorders - Symptoms such as abdominal pain, tenderness, fever, constipation, abdominal discomfort, and diarrhea should be considered early manifestations of serious gastrointestinal toxicity. Gastrointestinal (GI) reactions like hemorrhage and perforation, ileus and colitis, and some life-threatening conditions have been reported in patients treated with Cabazitaxel.

5. Risk of Nausea, Vomiting, Diarrhea, and Dehydration - Some patients who experience diarrhea with Cabazitaxel may be treated with common anti-diarrheal medications. Supportive treatment should be given to patients. It is important to rehydrate the patients and monitor their serum electrolyte levels. Dose reduction is important for grade 3 diarrhea.

6. Damage to the Peripheral Nerves - In cases of nerve damage, peripheral sensory neuropathy, paraesthesias, dysaesthesias, and peripheral motor neuropathy can occur in patients receiving Cabazitaxel.

7. Anemia - Caution measures should be taken in patients with anemia. Anemia has been reported in patients receiving Cabazitaxel. Hemoglobin and hematocrit should be checked before the indication of the drug and if patients have anemia or blood loss symptoms.

8. Renal Failure - Renal disorders have been associated with sepsis, severe dehydration due to diarrhea, vomiting, and obstructive uropathy. Renal failure, including cases of death, has been observed. It is recommended to take immediate actions to identify the causes and treat them accordingly.

9. Respiratory Disorders - Interstitial pneumonia and interstitial lung disease have been observed in many cases. Patients should be closely monitored, investigated, and appropriately treated if new pulmonary symptoms develop. Cabazitaxel therapy should be paused until the diagnosis is available. Symptomatic and supportive care should be indicated.

10. Risk of Cardiac Arrhythmias - Cardiac arrhythmias have been reported in patients with ongoing treatment, most commonly tachycardia and atrial fibrillation.

11. Elderly - Older adults (65 years of age or more) are more likely to have adverse reactions, low blood cell count, and low blood pressure, which can lead to unfortunate life-threatening conditions.

12. Patients with Liver Impairment - Treatment with Cabazitaxel is contraindicated in patients with hepatic impairment. The dose should be reduced for patients with mild hepatic impairment to avoid serious conditions.

Pre-Medication

Pre-medication is important to reduce the risk of getting severe hypersensitivity reactions. At least 30 minutes before administration of Cabazitaxel following medication can be given to the affected individual -

• Antihistamine (Diphenhydramine 25 mg).

• Corticosteroids (Dexamethasone 8 mg).

• H2 antagonist (Ranitidine 50 mg).

Drug Interactions

Drug interactions refer to the reaction in the body when one or more drugs are administered simultaneously, or vaccines are injected to avoid getting affected by certain types of disorders that can also react with some drugs and result in serious medical conditions. Therefore certain medicines should be used in a variety of ways. In these cases, the healthcare provider wants to change the dose, or other precautions may be necessary. When indicted for having these medicines, it is very important to consult the health care provider.

Indicating Cabazitaxel medicine with any of the following medicines is not recommended and can result in certain life-threatening conditions.

• Measles virus vaccine.

• Mumps virus vaccine.

• Rotavirus vaccine.

• Rubella virus vaccine.

• Varicella virus vaccine.

• Zoster vaccine.

Indication of Cabazitaxel with the following medicines is not recommended -

• Adenovirus vaccine.

• Atazanavir.

• Bacillus of Calmette and Guerin vaccine.

• Boceprevir.

• Ceritinib.

• Cholera vaccine.

• Clarithromycin.

• Cobicistat.

• Conivaptan.

• Delavirdine.

• Dengue tetravalent vaccine.

• Idelalisib.

• Indinavir.

• Influenza Virus Vaccine, Live.

• Itraconazole.

• Ketoconazole.

• Lopinavir.

• Nefazodone.

• Nelfinavir.

• Poliovirus Vaccine, Live.

• Posaconazole.

• Ritonavir.

• Saquinavir.

• Smallpox Vaccine.

• Telaprevir.

• Telithromycin.

• Tipranavir.

• Typhoid vaccine.

• Voriconazole.

• Yellow Fever Vaccine.

For Patients

What Is Prostate Gland?

The prostate gland is an organ with seminal vesicles and belongs to the male reproductive system. The prostate is a small gland and weighs around 28 grams. The seminal vesicles are two small paired glands. These glands are located on both sides of the prostate. The prostate gland is posterior to the bladder and inferior to the rectum. The prostate encircles the urethra. The urethra is a tube-like structure that helps in carrying urine from the bladder to the penis. Men with an enlarged prostate have difficulty urinating.

Prostate and seminal vesicles play the main job during ejaculation. Sperms are produced in the testicles and then move to the urethra. Simultaneously, fluid produced and stored in the prostate and the seminal vesicles also moves into the urethra and mix with the semen and ejaculates out of the penis by the urethra.

What Is Prostate Cancer?

Prostate cancer is considered an uncontrolled growth of cells in the prostate gland. The prostate is a small-sized gland in men, situated below the bladder and in front of the rectum, around the urethra. The urethra is a tube that carries urine out of the bladder. The prostate produces and stores a fluid that helps produce semen.

Prostate cancer is a common type of cancer seen in men all around the globe and often begins without symptoms. Prostate cancer can be slow-growing. However, many prostate cancers are more aggressive and can involve other internal organs, which can be life-threatening. The prostate cancer prognosis is greatly improved with early detection and personalized treatment.

Who Can Most Likely Get Affected?

Every man has a prostate and can develop prostate cancer. But it can also depend on some factors like -

• Age - The chance of developing prostate cancer increases as a person ages. Prostate cancer is rare in younger men aged under 50 years.

• Family History - The risk of prostate cancer is higher if prostate cancer runs in the family history.

• Race - African Americans are more likely to get prostate cancer. Even at a younger age.

What Are the Symptoms of Prostate Cancer?

Prostate cancer does not always cause symptoms. If it shows some symptoms, it may include:

• The urine stream becomes weak.

• Sudden urge to urinate.

• Urinating often, especially at night.

• Pain or a burning sensation when urinating.

• Blood in the urine or semen.

• Pain in the lower back, hips, or pelvis.

• Painful ejaculation.

Cabazitaxel Side Effects:

Important facts about the side effects of Cabazitaxel:

• Cabazitaxel's side effects are not common for everyone.

• Cabazitaxel side effects are often predictable regarding their onset, duration, and severity.

• Cabazitaxel side effects are often reversible and likely to improve after complete therapy.

• Cabazitaxel's side effects are quite manageable. There are many options to prevent the side effects of cabazitaxel.

The following side effects are common for patients taking Cabazitaxel:

• Low blood counts cause amenia, neutropenia, and thrombocytopenia.

• Diarrhea.

• Fatigue.

• Nausea.

• Vomiting.

• Constipation.

• Weakness.

• Abdominal pain.

• Presence of blood in the urine sample.

• Lack of appetite.

• Back pain.

• Damage to the peripheral nerves.

• Shortness of breath.

• Fever.

• Taste changes.

• Joint aches.

• Cough.

• Hair loss.

• Heartburn.

Infusion-related side effects include allergic reactions like rash, flushing, fever, and lower blood pressure. This rarely happens and usually occurs during the initial and final infusion. The patient should be closely monitored during the infusion, and if any signs of allergic reaction are observed, the treatment should stop immediately, and the patient should be under observation. Side effects on the drug administration site include darkening of the vein, redness of the skin, swelling of the vein, or pain.

For Doctors

Pharmacology

Indication

Cabazitaxel is indicated in patients with hormone-refractory metastatic prostate cancer previously treated with a Docetaxel-containing treatment regimen and did not respond.

Associated Conditions

Refractory or metastatic hormone-refractory prostate cancer.

Contraindications

• Bad infection.

• Caloric undernutrition.

• Dehydration.

• Anemia.

• Decreased blood platelets.

• Low levels of white blood cells are called neutrophils.

• Liver problems.

• Severe liver disease.

• Acute kidney failure.

• Inflammation of the bladder with hemorrhage.

• Vomiting.

• Excessive diarrhea.

• Pregnancy.

• Lung tissue problem.

Pharmacodynamics

Cabazitaxel has antineoplastic properties and is effective against Docetaxel-sensitive and insensitive cancers.

Mechanism of Action

Cabazitaxel is a microtubule inhibitor. Cabazitaxel binds to tubulin and promotes its conversion into microtubules while simultaneously inhibiting the destruction of microtubules. This results in the stabilization of microtubules, which causes mitotic and interphase cellular functions to temper. The cell is then unable to progress further in the cell cycle and holds up at metaphase, which results in the triggering apoptosis of the cancer cell.

Absorption

After administering the intravenous dose of Cabazitaxel 25 mg/m2 every three weeks in patients with prostate cancer, the mean Cmax in patients with metastatic prostate cancer was 226 ng/mL. 991 ng/mL in the mean AUC in patients with metastatic prostate cancer. Simply put, peak plasma time is one hour, peak plasma concentration is 226ng/mL, and AUC is 991 ng/mL. Administration with Prednisone does not affect the pharmacokinetic profile of Cabazitaxel.

The Volume of Distribution

The volume of distribution (Vss) was 4,864 at a steady state. Compared to other taxanes, it penetrates the CNS to a greater extent.

Protein Binding

Cabazitaxel holds a chemical bonding with human serum albumin and lipoproteins (89 to 92 %, respectively).

Metabolism

Cabazitaxel is mainly metabolized in the liver. In addition, it is metabolized by the CYP3A4/5 isoenzyme (80 % to 90 %) and a bit by CYP2C8, which results in 20 different metabolites which are detected in feces or urine. Two of these 20 metabolites belong to demethylate derivatives Cabazitaxel and are referred to as RPR112698 and RPR123142, respectively.

Route of Elimination

After administering a one-hour intravenous infusion of Cabazitaxel 25 mg/m2, almost 80 % of the administered dose was eliminated within two weeks. Cabazitaxel is mainly excreted in the feces, and 3.7% of the dose is excreted by the urine.

Half-life

Plasma concentrations of Cabazitaxel can be described by three compartments like, alpha, beta, and gamma, of the pharmacokinetic model with a half-life of 4 minutes, 2 hours, and 95 hours, respectively.

Clearance

Cabazitaxel slows plasma clearance by 48.5 L/h in patients with metastatic prostate cancer.

Adverse Effects

Indication of Cabazitaxel comes with some adverse effects -

• Anemia.

• Leukopenia.

• Neutropenia.

• Thrombocytopenia.

• Diarrhea.

• Fatigue.

• Nausea.

• Vomiting.

• Asthenia.

• Constipation.

• Abdominal pain.

• Hematuria.

• Anorexia.

• Back pain/arthralgia.

• Peripheral neuropathy.

• Pyrexia.

• Dyspnea.

• Cough.

• Dyspepsia.

• Alopecia.

• Peripheral edema.

• Weight loss.

• Dizziness.

• Headache.

• Urinary tract infection.

• Dysuria.

• Febrile neutropenia.

• Mucosal inflammation.

• Hypotension.

• Arrhythmia.

• Gastritis and intestinal obstruction.

• Interstitial pneumonia or pneumonitis.

• Interstitial lung disease.

• Acute respiratory distress syndrome.

• Bone marrow suppression.

• Renal failure.

• Renal and urinary disorders.

Toxicity

Administration of Cabazitaxel can cause side effects such as neutropenia, hypersensitivity reactions, gastrointestinal symptoms, and renal disorders. Anticipated overdose complications include exacerbating adverse reactions such as bone marrow suppression and gastrointestinal disorders. Cabazitaxel can also penetrate the blood-brain barrier.

Severe hypersensitivity reactions like hypotension, bronchospasm, and generalized rash or erythema have also been reported. If these reactions occur, the infusion should be immediately discontinued, and appropriate supportive treatment should be administered. Hence, cabazitaxel and other taxanes are contraindicated in patients with known hypersensitivity reactions.

Other toxicities include mild to moderate nausea and vomiting, severe diarrhea, neurotoxicity, fatigue, and alopecia. Neurotoxicity is also observed, including paresthesias, diminished deep tendon reflexes, and impaired vibratory sensations. Renal failure has been reported as generally associated with sepsis, dehydration, or obstructive uropathy. It is also embryotoxic and may cause life-threatening conditions.