PACLIALL

Indications

• Adjuvant treatment of operable node-positive and node-negative breast cancer
• Treatment of hormone-refractory metastatic prostate cancer
• Initial chemotherapy for metastatic breast cancer
• Treatment of advanced ovarian cancer in combination with cisplatin
• Initial chemotherapy of non-small cell lung cancer with cisplatin
• Treatment of metastatic gastric adenocarcinoma
• Treatment of locally advanced squamous cell carcinoma of the head and neck

Dosage

Children: Refer to the BNF for Children for detailed paediatric dosing guidelines.

Adults: Refer to product literature or local protocols for specific dosing information.

Mechanism of action

Paclitaxel interferes with the normal function of microtubule growth by hyper-stabilizing their structure. It binds to the beta subunit of tubulin, locking the microtubule structure in place and preventing disassembly. This disrupts the dynamic instability necessary for essential cellular functions, including mitosis, and promotes apoptosis in cancer cells by inhibiting the function of the apoptosis regulator Bcl-2.

Pharmacodynamics

Paclitaxel acts as an antineoplastic agent by promoting the assembly of microtubules and preventing their depolymerization. This results in the formation of abnormal microtubule structures and inhibits cellular processes essential for cell division and function. It is indicated for first-line and subsequent therapy in advanced ovarian carcinoma and other malignancies, demonstrating a significant ability to induce programmed cell death in cancer cells.

Pharmacokinetics

Paclitaxel is administered intravenously and exhibits a multi-compartment pharmacokinetic profile. It is extensively metabolized by the liver, primarily through cytochrome P450 enzymes. Its half-life can vary widely due to extensive protein binding and distribution in tissues. The drug's clearance is affected by hepatic function, necessitating monitoring in patients with liver impairment.

Contra-indications

• Severe hypersensitivity to paclitaxel or any excipients
• Severe hepatic impairment
• Pregnancy

Adverse effects

• Abdominal pain
• Alopecia
• Anaemia
• Appetite decreased
• Arrhythmia
• Arthralgia
• Asthenia
• Constipation
• Diarrhoea
• Dyspnoea
• Fluid imbalance
• Haemorrhage
• Hypersensitivity
• Hypertension
• Hypotension
• Increased risk of infection
• Myalgia
• Nausea
• Neutropenia
• Pain
• Peripheral neuropathy
• Sepsis
• Skin reactions
• Stomatitis
• Taste altered
• Thrombocytopenia
• Vomiting

Interactions

• Dabrafenib (severe - decreases exposure)
• Bosentan (severe - decreases exposure)
• Mitotane (severe - decreases exposure)
• Rifampicin (severe - decreases exposure)
• Selpercatinib (severe - increases exposure)
• St John's Wort (severe - decreases exposure)
• Berotralstat (moderate - increases concentration)
• Eliglustat (moderate - increases exposure)
• Sotorasib (moderate - increases exposure)
• Tucatinib (moderate - increases exposure)

Precautions

• Monitor liver function in hepatic impairment
• Caution in patients with acute porphyrias
• Caution in patients with pre-existing heart conditions

Pregnancy

Paclitaxel is contraindicated in pregnancy due to potential harm to the fetus.

Breast-feeding

Breastfeeding is not recommended during treatment with paclitaxel due to potential adverse effects on the infant.

Storage

Store in a refrigerator (2°C to 8°C). Protect from light. Do not freeze.

Formulations

• Paclitaxel 80mg/8ml concentrate for solution for infusion

Dosage

Children: Refer to specific drug formulations for appropriate dosing guidelines.

Adults: Refer to specific drug formulations for appropriate dosing guidelines.

Mechanism of action

The mechanism of action of particles in drug formulations is highly dependent on their composition and the intended drug. For instance, nanoparticles can enhance drug solubility, improve bioavailability, and enable targeted delivery. They can interact with biological membranes, facilitating translocation of drugs across cellular barriers, and can be engineered for specific interactions with cellular receptors or pathways.

Pharmacodynamics

The pharmacodynamics of drug particles involves their effects on the body and the mechanisms through which they exert therapeutic effects. This can include how the particles improve drug solubility and absorption, modulate drug release rates, and enhance cellular uptake. The interaction between drug particles and biological systems is influenced by factors such as particle size, surface charge, and the presence of surface modifications.

Pharmacokinetics

Pharmacokinetics of drug particles encompasses the absorption, distribution, metabolism, and excretion of the drug. The size and characteristics of the particles affect their absorption through biological membranes, with smaller particles typically having higher bioavailability. Distribution can also be modified by the particle size, impacting how quickly and effectively the drug reaches its target site. Metabolism may be altered by the physical state of the drug (e.g., solid vs. liquid) and its interaction with metabolic enzymes. Excretion pathways can vary based on the particle's properties, influencing the drug's half-life and overall therapeutic efficacy.

Pregnancy

The effects of particles can vary widely based on the specific type and context of exposure. General caution is advised during pregnancy, and specific advice should be sought based on the type of particles.

Breast-feeding

The effects of particles on breastfeeding depend on their nature. Consultation with a healthcare provider is recommended to assess any potential risks.

Storage

Storage conditions for particles depend on their specific type and intended use. Generally, they should be stored in a cool, dry place away from direct sunlight, and in secure containers to prevent contamination.

Mechanism of action

Paclitaxel interferes with the normal function of microtubule growth. Whereas drugs like colchicine cause the depolymerization of microtubules in vivo, paclitaxel arrests their function by having the opposite effect; it hyper-stabilizes their structure. This destroys the cell's ability to use its cytoskeleton in a flexible manner. Specifically, paclitaxel binds to the β subunit of tubulin. Tubulin is the "building block" of mictotubules, and the binding of paclitaxel locks these building blocks in place. The resulting microtubule/paclitaxel complex does not have the ability to disassemble. This adversely affects cell function because the shortening and lengthening of microtubules (termed dynamic instability) is necessary for their function as a transportation highway for the cell. Chromosomes, for example, rely upon this property of microtubules during mitosis. Further research has indicated that paclitaxel induces programmed cell death (apoptosis) in cancer cells by binding to an apoptosis stopping protein called Bcl-2 (B-cell leukemia 2) and thus arresting its function. Evidence suggests that paclitaxel also may induce cell death by triggering apoptosis. In addition, paclitaxel and docetaxel enhance the effects of ionizing radiation, possibly by blocking cells in the G2 phase, the phase of the cell cycle in which cells are most radiosensitive. Paclitaxel is an antimicrotubule antineoplastic agent. Unlike some other common antimicrotubule agents (e.g., vinca alkaloids, colchicine, podophyllotoxin), which inhibit microtubule assembly, paclitaxel and docetaxel (a semisynthetic taxoid) promote microtubule assembly. Microtubules are organelles that exist in a state of dynamic equilibrium with their components, tubulin dimers. They are an essential part of the mitotic spindle and also are involved in maintenance of cell shape and motility, and transport between organelles within the cell. By binding in a reversible, concentration-dependent manner to the beta-subunit of tubulin at the N-terminal domain, paclitaxel enhances the polymerization of tubulin, the protein subunit of the spindle microtubules, even in the absence of factors that are normally required for microtubule assembly (e.g., guanosine triphosphate [GTP]), and induces the formation of stable, nonfunctional microtubules. Paclitaxel promotes microtubule stability even under conditions that typically cause depolymerization in vitro (e.g., cold temperature, the addition of calcium, the presence of antimitotic drugs). While the precise mechanism of action of the drug is not understood fully, paclitaxel disrupts the dynamic equilibrium within the microtubule system and blocks cells in the late G2 phase and M phase of the cell cycle, inhibiting cell replication. ... Taxol induces tubulin polymerization and forms extremely stable and nonfunctional microtubules. Taxol has demonstrated broad activity in preclinical screening studies, and antineoplastic activity has been observed in several classically refractory tumors. These tumors include cisplatin resistant ovarian carcinoma in phase II trials and malignant melanoma and non-small cell lung carcinoma in phase I studies.

Pharmacodynamics

Paclitaxel is a taxoid antineoplastic agent indicated as first-line and subsequent therapy for the treatment of advanced carcinoma of the ovary, and other various cancers including breast cancer. Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or "bundles" of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.