- Paclitaxel was discovered as part of a National Cancer Institute program in which extracts of thousands of plants were screened for anticancer activity.
- In 1963, a crude extract of the bark of the Pacific yew tree, Taxus brevifolia, was shown to have impressive activity in preclinical tumor models. Procurement and stability issues hindered the availability of paclitaxel for clinical use.
- The production of a semisynthetic form of paclitaxel using the precursor 10-deacetyl-baccatin III, which is found in the needles of the European yew, Taxus baccata, has allowed large supplies to be produced.
Mechanism of Action
- Binds to the interior surface of the microtubule lumen.
- Profoundly alters the tubulin dissociation rate constants at both ends of the microtubule, suppressing treadmilling and dynamic instability. –MITOTIC ARREST
- However, in sharp contrast to the vinca alkaloids, they do not alter the association rate constants and the process of tubulin polymerization
Mechanism of Resistance
- Alterations in tubulin with decreased binding affinity for drug.
- Multidrug-resistant phenotype with increased expression of P170 glycoprotein. Results in enhanced drug efflux with decreased intracellular accumulation of drug.
- Cross-resistant to vinca alkaloids, anthracyclines and VP-16.
- Poorly soluble and not orally bioavailable.
- Distributes widely to all body tissues, including third-space fluid collections such as ascites.
- Negligible penetration into the CNS.
- Extensive binding (90%) to plasma and cellular protein
- Non linear pharmacokinetics (absence of a dose–response relationship: increasing the dose increases toxicity without an accompanying enhancement in efficacy ). Longer infusions-more neutropenia and neurotoxicity
- Metabolized extensively by the hepatic P450 microsomal system.
- About 70%–80% of drug is excreted via fecal elimination.
- Renal clearance is less than 10%
- Terminal elimination half-life ranges from 9 to 50 hours.
- Each ml of paclitaxel solution contains 6 mg of paclitaxel and 527 mg polyoxyl 35 castor oil, dehydrated absolute alcohol
- 30 mg/ 5ml vial
- 100 mg/16.66 ml vial
- 260 mg/43.33 ml vial
- Should be diluted with NS or 5% D to a final concentration of 0.3 to 1.2 mg/ml.
Problems with Conventional Paclitaxel
- Cremaphor EL (CrEL), a nonionic surfactant poly-oxy-ethylated castor oil mixed 1:1 with dehydrated ethanol.
- CrEL-paclitaxel formulation needs special infusion set to minimize exposure to di(2-ethylhexyl)phthalate (DHEP), which may be leached from standard polyvinyl chloride sets.
- Prolonged infusion times and premedications with corticosteroids and antihistamine agents are required to reduce hypersensitivity reactions.
- CrEL is also shown to cause neutropenia and prolonged peripheral neuropathy related to axonal degeneration.
- Cremophor EL entraps paclitaxel into circulating micelles, which reduces its availability and delivery into tumors .
- Micelle formation with solvent-based paclitaxel results in nonlinear kinetics and the absence of a dose–response relationship: increasing the dose increases toxicity without an accompanying enhancement in efficacy.
- Should be given in glass bottle or polyethylene containers.
- Use polyvinyl chloride ( PVC ) free IV set i.e. use polyethylene lined IV set with 0.2 microm filter. These precautions are needed to avoid leaching of plasticiser DEHP ( Di Ethyl Hexyl Phthalate ) from PVC infusion bags or sets.
Why PVC free bottle
- DEHP (DEHP), a plastic-softening phthalate, has been used as a plasticiser in intravenous tubing and bags, catheters, nasogastric tubes, dialysis bags and tubing, and blood bags and transfusion tubing .
- DEHP provides the PVC with desired mechanical properties flexibility, strength, suitability for use at a wide range of temperatures, resistance to kinking, optical clarity.
- When used in PVC plastic, DEHP is loosely chemically bonded to the plastic and readily leaches into blood and plasma.
- Castor oil (Cremophor EL), dramatically increase the rate of DEHP extraction from PVC bags .
- This leaching of DEHP increases the risk of certain adverse health outcomes and can damage the liver, kidneys, lungs, and reproductive system.
- Complete infertility in females and reduced fertility in males. Seminiferous tubule damage with adverse effects on sperm numbers, motility, and morphology. Reduced Male reproductive organ weights.
- Ovarian cancer (with platinum for first-line treatment of advanced carcinoma of the ovary; single agent for subsequent therapy of advanced carcinoma of the ovary).
- Breast cancer (single agent for adjuvant treatment of node-positive breast cancer administered sequentially to standard doxorubicin-containing combination chemotherapy; single agent for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy
- Non-small cell lung cancer (with cisplatin of non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy)
- AIDS-related Kaposi sarcoma (single agent for second-line treatment)
- Small cell lung cancer, head and neck cancer, esophageal cancer, bladder cancer, treatment of unknown primary.
- Metabolism of paclitaxel may be affected by inhibitors and/or activators of the liver cytochrome P450 CYP3A4 and CYP2C8 enzyme systems.
- Phenytoin, phenobarbital—Accelerate the metabolism of paclitaxel resulting in lower plasma levels of drug
- Administration of cisplatin prior to paclitaxel leads to greater myelosuppression than administrating it after. In patients receiving cisplatin prior to paclitaxel there is 33 % decrease in paclitaxel clearance.
- Paclitaxel reduces the clearance of doxorubicin causing more profound myelosuppression.
- Cyclophosphamide—Myelosuppression is greater when cyclophosphamide is administered before paclitaxel.
- Dose should be reduced if serum bilirubin is > 1.6 times ULN and liver enzymes > 10 times ULN. .
- Renal impairment: no dose adjustments necessary
It is the principal toxicity of paclitaxel.(20%)
- Major hypersensitivity reactions occur in 3% of patients with effective prophylaxis.
- Dexamethasone, 20 mg orally or intravenously, 12 and 6 hours before treatment; an H1-receptor antagonist (e.g., diphenhydramine, 50 mg intravenously) 30 minutes before treatment; and an H2-receptor antagonist (e.g., cimetidine, 300 mg; famotidine, 20 mg; or ranitidine, 150 mg intravenously) 30 minutes before treatment.
- A single dose of a corticosteroid (dexamethasone, 20 mg intravenously) administered 30 minutes before treatment also appears to confer effective prophylaxis against major hypersensitivity reactions
Peripheral sensory neuropathy
- At cumulative doses in excess of 1,400 mg/m2 / more than 250 mg/m2 infused over ≥24 hours .
- With lower doses of paclitaxel (135-200 mg/m2) , neuropathy is less common.
- Partially reversible.
- Neuroprotective agents: Amifostine; Glutamate; Nerve Growth Factor; Insulin-like Growth Factor; Acetyl-L-carnitine; oral vitamin E at a daily dose of 600 mg/day
- Treatment : Amitryptyline, Acetyl-L-carnitine, Pregabalin, gabapentin combined with nonsteroidal anti-inflammatory drugs such as ibuprofen, can provide some relief to painful paclitaxel neuropathy.
- Transient myalgias
- Transient sinus bradycardia, can be observed in up to 30% of patients.
- Onycholysis. Mainly observed in those receiving 6 courses on the weekly schedule. Not seen with the every-3-week schedule