Docetaxel

Docetaxel is an antineoplastic agent belonging to the pharmacological class of taxanes or microtubule damaging agents.

Docetaxel is FDA-approved for the treatment of breast cancer, non-small cell lung cancer, prostate cancer, gastric adenocarcinoma, and head and neck cancer.

Docetaxel swiftly shows dose-proportional kinetics, distributing into peripheral compartments, mainly binding to plasma proteins, metabolized through CYP3A4, and primarily eliminated through faeces, with limited urinary excretion.

The most common side effects of Docetaxel include breathlessness, constipation, oedema (swelling), infection, loss of appetite, muscle pain, nail disorder, pain, and weakness.

Docetaxel is available as an injectable solution.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Docetaxel is an antineoplastic agent belonging to the pharmacological class of taxanes or microtubule damaging agents.

Docetaxel disrupts microtubule growth's regular process. In contrast to medications such as colchicine, which depolymerizes microtubules in vivo, Docetaxel hyper-stabilizes their structure, thereby stopping their function. This eliminates the cell's capacity to make flexible use of its cytoskeleton. Docetaxel specifically binds to tubulin's β-subunit. Microtubules' "building block" is tubulin, and docetaxel binding secures these building blocks. The ensuing microtubule/docetaxel complex is incapable of breaking down. Because microtubules' role as the cell's transportation network depends on their ability to shorten and lengthen (a process known as dynamic instability), this harms cell function. During mitosis, for instance, chromosomes depend on this microtubule characteristic. Additional studies have shown that Docetaxel causes cancer cells to undergo programmed cell death, or apoptosis, by attaching to and inhibiting the activity of the protein Bcl-2 (B-cell leukaemia 2), which prevents apoptosis.

Docetaxel is available as an injectable solution.

Injectable solution: To be administered by healthcare professionals through intravenous infusion over 1 hour after appropriate dilution.

Parenterally: Docetaxel is administered parenterally via intravenous infusion, diluting it suitably and delivering it over 1 hour at an initial dose of 75 mg/m². Utilize sterile equipment to prevent infections.Administer  intravenous infusion using an in-line filter with a pore size of 0.22 microns. Prioritize premedication with oral corticosteroids before each Docetaxel Injection to minimize fluid retention. Ensure vigilant monitoring during and after administration to effectively manage any immediate or delayed reactions. Continuous cardiac monitoring is essential due to the risk of conduction abnormalities. The preferred administration route is intravenous infusion.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Docetaxel is available as an injectable solution.

Administer intravenously over 1 hr every three weeks.

NSCLC: 75 mg/m2 single agent after platinum therapy fails.

NSCLC: 75 mg/m2 of chemotherapy, followed by 75 mg/m2 of cisplatin.

HRPC: 75 mg/m2 plus 5 mg of prednisone taken twice daily indefinitely.

Day 1 only: 75 mg/m2 of GC, 75 mg/m2 of cisplatin, and 750 mg/m2 of fluorouracil administered intravenously daily for 24 hours (days 1–5) beginning after the cisplatin infusion.

SCCHN: 75 mg/m2 and cisplatin 75 mg/m2 intravenously (day 1), with a 24-hour intravenous infusion of fluorouracil 750 mg/m2 per day (days 1–5), starting at the end of the cisplatin infusion; for four cycles.

SCCHN: 75 mg/m2, 100 mg/m2 intravenously on day 1, and 1000 mg/m2 intravenously every day for 24 hours as an intravenous infusion on days 1-4; for three cycles.

• Use oral corticosteroids as a preventive measure.

• Modify dosage as necessary

Adhere to dietary recommendations when taking Docetaxel for enhanced safety. Maintain a fibre diet from fruits, vegetables, and whole grains. Incorporate fish, soy, tomatoes, Brussels sprouts, kale, broccoli, and omega-3 fatty acid oils like olive oil, known to reduce prostate cancer risk. Embrace a plant-based diet, emphasizing whole grains and legumes while limiting fats, especially during breast cancer phases. Avoid grilled or red meats, saturated fats from animal sources, milk, and dairy. Establish consistent eating intervals, favouring whole grains, fruits, veggies, and low-fat dairy.

The dietary restriction should be individualized as per patient requirements.

The adverse reactions related to Docetaxel can be categorized as:

The clinically relevant drug interactions of Docetaxel are briefly summarized here.

It is advised to refrain from using Docetaxel concurrently with strong CYP3A4 inhibitors such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole. In cases where it is not possible to avoid such concurrent use, docetaxel dosage adjustments may be appropriate, and careful toxicity monitoring should be conducted.

The common side effects of Docetaxel include:

Breathlessness

Constipation

Headache

Fatigue

Dizziness

Drowsiness

Nausea

Indigestion

Vomiting

Pain/swelling at the injection site

Infection

Insomnia (sleeplessness)

Fever

Loss of appetite

Muscle pain

Nail disorder

Pregnancy Category D (FDA): Use in situations where there is no safer medication available and life is in danger. Evidence that human fetal risk exists.

When given to a pregnant woman, docetaxel injection may be harmful to the fetus.

When Docetaxel was given to pregnant rats and rabbits during the organogenesis stage, it resulted in embryofetal toxicities, including intrauterine death. On a body surface area basis, embryofetal effects were observed in animals at doses as low as 1/50 and 1/300 of the recommended human dose.

Pregnant women utilizing docetaxel injection have not been the subject of sufficient, carefully monitored studies. The patient should be informed of the possible risk to the fetus if Docetaxel is administered during pregnancy or if the women gets pregnant while taking this medication. It should be recommended to women who are or may become pregnant to avoid getting pregnant while receiving docetaxel injection therapy.

The presence of Docetaxel in human milk and its effects on the production of milk and the breastfed child is unknown. No lactation studies in animals have been carried out. Women are advised not to breastfeed during treatment and for two weeks following the last dose due to the severe adverse reactions that could occur in a breastfed child from docetaxel exposure, including toxic death, hepatotoxicity, neutropenia, and acute myeloid leukaemia.

As per FDA, the safety and efficacy of Docetaxel in Pediatric patients have not been established.

In older patients, especially those with poor performance status, or in patients with non-life-threatening indolent diseases (e.g., relatively asymptomatic metastatic disease limited to the bone), specific toxicities associated with docetaxel therapy may occur more frequently and with greater severity. It is recommended to use caution when choosing a dose for elderly patients due to the higher frequency of concomitant diseases, decreased hepatic, renal, and/or cardiac function, and drug therapy in this population.

Renal impairment: No dosage adjustment is required.

If the alkaline phosphatase (AP) or AST/ALT are more than five times the upper limit of normal, do not administer the drug.

Not recommended in patients with bilirubin >ULN and those with concurrently elevated AST and/or ALT >1.5 × ULN and alkaline phosphatase >2.5 × ULN.

In the case of AST/ALT >2.5-5x ULN and AP ≤2.5x ULN, lower the dosage by 20%.

20% dose reduction if AP >2.5-5x ULN and AST/ALT >1.5-5x ULN

If a patient has a hepatic impairment, take into account the alcohol content of Docetaxel.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Docetaxel.

Overconsumption of Docetaxel could lead to bone marrow suppression, peripheral neurotoxicity, and mucositis.

There is no specific antidote or treatment for overdosage of Docetaxel, so treatment typically involves symptomatic and supportive measures, closely monitoring vital signs, frequent assessment of blood counts, and appropriate management of potential complications such as infections or myelosuppression. Consideration of dose reduction or discontinuation might be necessary based on the severity of symptoms. Hemodialysis is not practical due to the high degree of Docetaxel protein binding. Administering granulocyte colony-stimulating factor (G-CSF) may help with neutropenia. Timely medical intervention plays a crucial role in managing Docetaxel overdose, ensuring careful monitoring and proper care to address symptoms and prevent complications.

Docetaxel stabilizes microtubules and encourages their assembly from tubulin dimers by inhibiting depolymerisation. The standard dynamic reorganization of the microtubule network, which is necessary for critical interphase and mitotic cellular functions, is inhibited due to this stability. Docetaxel also causes multiasters of microtubules during mitosis and aberrant arrays or "bundles" of microtubules during the cell cycle.

Absorption: In phase 1 studies, Docetaxel's pharmacokinetics revealed dose-proportional behaviour from 70 mg/m2 to 115 mg/m2 with infusion durations of 1 to 2 hours. Its pharmacokinetic model is consistent with a three-compartment structure featuring half-lives for distinct phases. Clearance averaged 21 L/h/m2.

Distribution: After administration, Docetaxel's rapid decline indicates peripheral distribution, while its terminal phase reflects a slower efflux from peripheral compartments. The steady-state volume of distribution was approximately 113 L. The drug predominantly binds to plasma proteins, primarily α1-acid glycoprotein, albumin, and lipoproteins.

Metabolism: Cytochrome P450 3A4 is responsible for Docetaxel's metabolism. Its metabolic pathway can be altered by drugs interacting with, inducing, inhibiting, or being metabolized by CYP3A4.

Elimination: Oxidative metabolism leads to Docetaxel's elimination via urine and faeces. Fecal excretion remains the primary route, accounting for about 75% of administered radioactivity, primarily as metabolites within the first 48 hours. About 6% is excreted through urine within seven days.