Docetaxel

Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-cell lung cancer.[5] It may be used by itself or along with other chemotherapy medication. It is given by slow injection into a vein.[6]

Common side effects include hair loss, cytopenia (low blood cell counts), numbness, shortness of breath, nausea, vomiting, and muscle pains.[6] Other severe side effects include allergic reactions and future cancers.[6] Docetaxel induced pneumotoxicity is also a well recognized adverse effect which has to be identified timely and treated after withholding the drug.[7] Side effects are more common in people with liver problems.[6] Use during pregnancy may harm the fetus.[6] Docetaxel is in the taxane family of medications.[8] It works by disrupting the normal function of microtubules and thereby stopping cell division.[6]

Docetaxel was patented in 1986 and approved for medical use in 1995.[9] It is on the World Health Organization's List of Essential Medicines.[10] Docetaxel is available as a generic medication.[6]

Medical uses

Docetaxel is used in the treatment of various cancers, including breast, lung, prostate, gastric, head and neck, and ovarian cancer.[6] Clinical data have shown docetaxel to have cytotoxic activity against breast, colorectal, lung, ovarian, prostate, liver, renal, gastric, and head and neck cancers and melanoma. In hormone-refractory prostate cancer docetaxel improves life expectancy and overall life quality.[11]

The optimal dose scheduling of taxanes remains unconfirmed, but most studies find significant mortality benefit following either a three-week or a one-week administration schedule. While a 2010 article in Current Clinical Pharmacology states, "weekly administration has emerged as the optimal schedule," the official docetaxel package insert recommends administration every three weeks.[12]

Outcomes

Treatment with docetaxel increases survival time in people with certain types of cancer. While some clinical trials show median survival times to be increased by approximately only three months, the range of survival time is large. Many people survive beyond five years with treatment from docetaxel, however it is difficult to attribute these findings directly to treatment with docetaxel.

Side effects

Docetaxel is a cytotoxic chemotherapeutic agent. As with all chemotherapy, adverse effects are common, and many side effects have been documented. Because docetaxel is a cell-cycle-specific agent, it is cytotoxic to all dividing cells in the body.[17] This includes tumour cells as well as hair follicles, bone marrow and other germ cells. For this reason, common chemotherapy side effects such as hair loss occur; sometimes this can be permanent. North west France are conducting a survey to establish exactly how many people are affected in this way. Independent studies show it could be as high as 6.3%, which puts it in the 'common and frequent' classification.[17]

Haematological adverse effects include neutropenia (95.5%), anaemia (90.4%), febrile neutropenia (11.0%) and thrombocytopenia (8.0%). Deaths due to toxicity accounted for 1.7% of the 2045 patients, and incidence was increased (9.8%) in patients with elevated baseline liver function tests (liver dysfunction).

The use of docetaxel during chemotherapy, especially when given weekly, may lead to complications with the lacrimal drainage system. The mechanism for this problem seems to be secretion of docetaxel by the lacrimal gland which can then cause stenosis, or narrowing, of the punctum and canalicular outflow system.[18]

Chemistry

Docetaxel is of the chemotherapy drug class taxane and is a semi-synthetic analogue of paclitaxel (Taxol), an extract from the bark of the rare Pacific yew tree, Taxus brevifolia.[22] Due to scarcity of paclitaxel, extensive research was carried out leading to the formulation of docetaxel – an esterified product of 10-deacetyl baccatin III, which is extracted from the renewable and more readily available leaves of the European yew tree.

Docetaxel differs from paclitaxel at two positions in its chemical structure. It has a hydroxyl functional group on carbon 10, whereas paclitaxel has an acetate ester, and a tert-butyl carbamate ester exists on the phenylpropionate side chain instead of the benzamide in paclitaxel. The carbon 10 functional group change causes docetaxel to be more water-soluble than paclitaxel.[22]

Formulations and compositions

Docetaxel is a white powder and is the active ingredient available in 20 mg and 80 mg Taxotere single-dose vials of concentrated anhydrous docetaxel in polysorbate 80.[22]

Pharmacokinetics

Absorption and distribution

Oral bioavailability has been found to be 8% ±6% on its own and, when co-administered with cyclosporine, bioavailability increased to 90% ± 44%.[25] In practice, docetaxel is administered intravenously only to increase dose precision.[22][23][26][27] Evaluation of docetaxel pharmacokinetics in phase II and III clinical studies were with 100 mg/m2 dosages given over one-hour infusions every three weeks.[22]

Mechanism of action

Molecular target

Docetaxel binds to microtubules reversibly with high affinity and has a maximum stoichiometry of 1 mole docetaxel per mole tubulin in microtubules.[34] This binding stabilizes microtubules and prevents depolymerisation from calcium ions, decreased temperature and dilution, preferentially at the plus end of the microtubule.[34] Docetaxel has been found to accumulate to higher concentration in ovarian adenocarcinoma cells than kidney carcinoma cells, which may contribute to the more effective treatment of ovarian cancer by docetaxel.[35][34] It has also been found to lead to the phosphorylation of oncoprotein bcl-2, which is apoptosis-blocking in its oncoprotein form.[35]

Society and culture

Discovery, regulation and marketing

Docetaxel is marketed worldwide under the name Taxotere by Sanofi-Aventis[39] as well as Docefrez by Sun Pharma Global and Zytax by Zydus.[40] Annual sales of Taxotere in 2010 were €2.122 billion (US$3.1 billion). The patent expired in 2010.

Docetaxel was developed by Rhône-Poulenc Rorer (now Sanofi-Aventis) following from the discoveries of Pierre Potier at CNRS at Gif-sur-Yvette during his work on improvements to the production of paclitaxel (Taxol) using the local European yew.[41]

Costs

In the UK (in 2009) The cost of six cycles (18 weeks) of docetaxel at a dose of 75 mg/m2 IV every 21 days is £5,262 (based on an average

References

Docetaxel Use During Pregnancy Drugs.com, 4 June 2020, retrieved 29 October 2020^
Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017 Therapeutic Goods Administration (TGA), 21 June 2022, retrieved 30 March 2024^
Taxotere- docetaxel injection, solution, concentrate

Contraindications and patient factors

Docetaxel is contraindicated for use with patients with a baseline neutrophil count less than 1500 cells/μL, a history of severe hypersensitivity reactions to docetaxel or polysorbate 80, severe liver impairment and pregnant or breast-feeding women.

Side effects are experienced more frequently by patients of 65 years or older, but dosage is usually not decreased. Kidney failure is thought not to be a significant factor for docetaxel dosage adjustment. Patients with hepatic insufficiency resulting in serum bilirubin greater than the upper limit of normal (ULN) should not be administered docetaxel, though this is not a stated contraindication. Dosage should be reduced by 20% in people who develop grade 3 or 4 diarrhea following exposure to docetaxel, hepatotoxicity defined by liver enzymes at levels greater than five times the ULN, and grade 2 palmer-planter toxicity.

Paediatric trials of docetaxel have been limited, and so safety of use in patients under 16 years has not been established.

Pregnancy

Based on the limited data available, docetaxel appears to be safe in pregnancy if administered during the second and third trimesters; however, maternal and fetal risks should be weighed against benefits to determine the appropriate course of action.[19][20] As with all chemotherapeutic agents, docetaxel administered to pregnant animals causes a variety of embryofetal toxicities, including death, when given during the period of organogenesis. Yet adequate studies investigating maternal and fetal effects in humans are lacking. One small systematic review that examined the use of taxanes to treat breast cancer in pregnancy showed that, out of 19 patients, only three congenital malformations occurred.[21] Two cases of cerebral ventriculomegaly observed in the study were documented prior to the administration of chemotherapy, suggesting an alternate cause of congenital malformation. The third case involved pyloric stenosis in an infant whose mother received a combination regimen of docetaxel, doxorubicin, cyclophosphamide and paclitaxel; because the fetus was exposed to multiple drugs in utero, it remains difficult to identify docetaxel as the causative teratogenic agent.[21] Further studies are needed to better assess the safety of docetaxel in pregnancy and determine appropriate dosing in pregnant women.

Drug interactions

Drug interactions may be the result of altered pharmacokinetics or pharmacodynamics due to one of the drugs involved. Cisplatin, dexamethasone, doxorubicin, etoposide, and vinblastine are all potentially co-administered with docetaxel and did not modify docetaxel plasma binding in phase II studies. Cisplatin is known to have a complex interaction with some CYPs and has in some events been shown to reduce docetaxel clearance by up to 25%. Anticonvulsants induce some metabolic pathways relevant to docetaxel. CYP450 and CYP3A show increased expression in response to the use of anticonvulsants and the metabolism of docetaxel metabolite M4 is processed by these CYPs. A corresponding increase in clearance of M4 by 25% is observed in patients taking phenytoin and phenobarbital, common anticonvulsants.

Erythromycin, ketoconazole and cyclosporine are CYP3A4 inhibitors and therefore inhibit the metabolic pathway of docetaxel. When used with anticonvulsants, which induce CYP3A4, an increased dose of docetaxel may be required.

Pre-treatment with corticosteroids has been used to decrease hypersensitivity reactions and oedema in response to docetaxel and has shown no effect on the pharmacokinetics of docetaxel. The efficacy of docetaxel was improved by treatment with oral capecitabine, and after more than 27 months follow-up the survival benefit has been confirmed. Doxorubicin was combined with docetaxel in one study of 24 patients and resulted in an increased AUC of docetaxel by 50 to 70%, indicating doxorubicin may affect the disposition of docetaxel. Etoposide has also been shown to decrease docetaxel clearance, though patient numbers for this observation have been low.

Prednisone given with docetaxel led to improved survival, quality of life and pain management in patients with hormone-refractory prostate cancer.[13]

Metabolism and excretion

Docetaxel is mainly metabolised in the liver by the cytochrome P450 CYP3A4 and CYP3A5 subfamilies of isoenzymes.[22][32][33] Metabolism is principally oxidative and at the tert-butylpropionate side chain, resulting first in an alcohol docetaxel (M2), which is then cyclised to three further metabolites (M1, M3 and M4).[33] M1 and M3 are two diastereomeric hydroxyoxazolidinones and M4 is an oxazolidinedione. Phase II trials of 577 patients showed docetaxel clearance is related to body surface area and to hepatic enzyme and alpha1 acid glycoprotein plasma levels.[28] The following model represents docetaxel clearance in humans:

CL = BSA · (22.1 − 3.55·AAG − 0.095·AGE + 0.2245·ALB) · (1 − 0.334·HEP12)

where CL is total body clearance (L/h), BSA is total body surface area (m2), AAG and ALB represent alpha1 acid glycoprotein and albumin plasma concentrations (g/L) respectively, and AGE is the patients age (years).[22] HEP12 represents a measure of hepatic dysfunction, affecting clearance of docetaxel. This final model accounted for a modest proportion of patients and identified most of the patients varying from the model (population median of CL = 35.6 L/h) as having hepatic dysfunction, indicating hepatic function as the most unpredictable factor with regards to clearance variability.[22]

Patients with significant hepatic dysfunction had an approximately 30% decrease in clearance of docetaxel and were also at a higher risk of toxicity poisoning from docetaxel treatment.[22] Clearance has been shown from population pharmacokinetic studies to decrease significantly with age, increased alpha1 acid glycoprotein and albumin concentrations and decreased body surface area.[22]

Renal impairment is unlikely to affect metabolism or excretion of docetaxel as renal excretion contributes less than 5% of elimination.[22] Limited data is available for docetaxel use in children with dosage between 55 and 75 mg/m2. Two paediatric studies have taken place that show a mean clearance of 33 L/h/m2 and concentration-time profiles best fitted by a two-compartmental model of distribution and elimination. Mean distribution half-life was 0.09 hours and mean elimination half-life was 1.4 hours in paediatric studies.[22]

Biodistribution of 14C-labelled docetaxel in three patients showed the bulk of the drug to be metabolised and excreted in bile to the faeces.[22] Of the radioactively labelled docetaxel administered, 80% was eliminated to the faeces with 5% in the urine over seven days, an indication that urinary excretion of docetaxel is minimal. Saliva contributed minimal excretion and no excretion was detected through pulmonary means.[22] The terminal half-life of docetaxel was determined as approximately 86 hours, through prolonged plasma sampling, contrary to the clinically stated terminal half-life of 10–18 hours.[25][31]