Paclitaxel

Paclitaxel is a drug with antitumor properties, produced semi-synthetically from natural raw materials obtained from Taxus baccata, the yew tree - a red tree from the yew family.

Its main area of application is in the field of those medications that are prescribed for chemotherapy to patients with oncological diseases. This antitumor agent is included in treatment regimens for malignant lesions of the lungs, larynx, mucous membranes of the nasopharynx and oral cavity, breast cancer, ovarian oncology, etc.

This drug, being a potent mitotic inhibitor, produces a stimulating effect on the processes in which dimeric tubulin molecules are involved in the assembly of microtubules. The use of Paclitaxel also helps to stabilize their structure and leads to a decrease in the rate of dynamic reorganization at the interphase stage, which causes a violation of cellular miotic function. As a result of its use, the occurrence of abnormal clusters created by microtubules is induced throughout the life cycle of cells, and in addition, multiple stellate clusters of microtubules are formed during mitosis.

Further developments are underway of new regimens and combinatorial features for the administration of this drug, which is very promising in terms of ensuring high individualization of chemotherapy based on molecular genetic typing of tumor formations.

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Indications Paclitaxel

Indications for the use of Paclitaxel are determined by its high degree of effectiveness as a drug among those used to treat all kinds of oncology.

So it is advisable to use it in ovarian cancer. In this case, the drug is included in the first-line therapy for a widespread form of this malignant lesion, or for a residual tumor formation not exceeding 1 centimeter. In addition, the combination of Paclitaxel and cisplatin is used after laparotomy. Ovarian cancer with second-line therapy involves the use of the drug in the presence of metastases and insufficient achieved therapeutic effect produced by standard therapeutic measures.

Indication for the use of Paclitaxel may be the presence of breast cancer. Mainly, when there are lesions of the lymph nodes after the end of adjuvant treatment, standard combination therapy; if the disease relapsed within a six-month period from the moment when adjuvant therapy was started. As a second-line therapy - for metastatic phenomena of breast cancer in the event that the adopted standard therapeutic measures have shown their inadequacy.

Furthermore, the rationale for including this drug in the treatment regimen as second-line therapy is the lack of the desired effect of liposomal anthracycline therapy in connection with Kaposi's sarcoma in AIDS.

Paclitaxel is also indicated for non-small cell lung cancer in first-line therapy. Here, cystoplatin is included in the combination. But the drug is prescribed only to those patients who are not supposed to undergo surgical treatment and X-ray therapy is not envisaged.

Other cases where the use of Paclitaxel may be justified include squamous cell cancer of the neck and head, transitional cell bladder cancer, malignant tumors in the esophagus, and leukemia.

Thus, based on all the above, it becomes obvious that the indications for the use of Paclitaxel cover a considerable number of cases of oncological diseases. In each of them, the drug exhibits one or another, but, as a rule, quite high, degree of its effectiveness as part of complex cancer treatment.

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Release form

Paclitaxel is available in the form of a concentrate, which is used to prepare a solution for subsequent administration by intravenous infusion.

1 milliliter of the drug contains paclitaxel 6 milligrams. In addition to this main active component, the composition contains various auxiliary substances: nitrogen, anhydrous ethanol, purified macrogolglycerol ricinoleate.

The concentrate is contained in a bottle made of transparent hydrolytic glass class I. The capacity of the bottle may vary and is 5 or 16.7 milliliters, respectively. The stopper on the bottle is made of bromobutyl, on top of which an aluminum shell is rolled to form a cap, which has a polypropylene lid.

The bottle is placed in a cardboard box, where the manufacturer also places a folded sheet containing instructions for use of the drug Paclitaxel. As for the number of bottles in such a package, it should be noted that it also differs in a certain variety. So if you open the box, you will find only a single 30-milligram bottle, which contains 5 ml of the drug, or, in a larger package, there may be 10 bottles of similar capacity. An option is also offered as 1 bottle per 100 mg - respectively 16.7 milliliters. The treatment regimen in which Paclitaxel is used, the prescribed dosage, the frequency of use can be different and strictly individual for each specific patient, due to which one or another form of release of the drug can be the most convenient.

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Pharmacodynamics

Pharmacodynamics Paclitaxel is manifested in the antitumor pharmacological action of the drug. Its use produces the effect of inhibiting mitosis processes, and also has a cytotoxic effect. Entering into specific connections with beta-tubulin microtubules, it causes violations of the depolymerization of this protein, which is of key importance.

The effect of Paclitaxel is to suppress the normal dynamic reorganization of the microtubule network. This is critical when interphase occurs, and without which cells are unable to function during mitosis.

A characteristic feature of the drug's pharmacology is also that it leads to the formation of several centrioles in the mitosis phase. Paclitaxel promotes the formation of abnormal bundles by microtubules throughout the entire period of the cell cycle, and during mitosis they form clusters that resemble stars in their appearance - asters.

Pharmacodynamics Paclitaxel is also characterized by the suppression of hematopoietic processes in the bone marrow. In addition, as is evident from the results of experimental studies, the drug has embryotoxic properties and can lead to a decrease in reproductive function.

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Pharmacokinetics

The essence of the processes that characterize the pharmacokinetics of Paclitaxel is as follows.

As a result of intravenous administration of the drug, its concentration in the blood plasma begins to decrease, in a manner consistent with biphasic kinetics.

In order to determine the specific pharmacokinetic properties of Paclitaxel, studies were conducted on processes occurring 3 and 24 hours after its administration. The doses used were 135 and 175 milligrams per square meter, respectively. Based on the results obtained, it was possible to state that with an increase in the dose at which the infusion was carried out, after more than 3 hours, the pharmacokinetics of the drug became nonlinear. A 30 percent increase in dosage, i.e. from 135 to 175 mg/m², resulted in an increase in Cmax by 75 percent, and AUC by 81.

Conducting several repeated courses of treatment, as was also found, does not cause a tendency for a cumulative effect to occur in connection with taking the drug.

In addition, it was found that Paclitaxel binds to proteins by 89-98 percent.

The pharmacokinetics of Paclitaxel have not been sufficiently studied to date. Available data only suggest that it is biotransformed in the liver, resulting in the formation of hydroxylated metabolites. The drug leaves the body with bile excretion.

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Dosing and administration

The method of administration and dosage of Paclitaxel are regulated by a number of practical guidelines that must be followed when dealing with this drug.

It should be noted that the stage of treatment, when its direct administration begins, should be preceded by a certain preparatory period, during which each patient without exception who is prescribed Paclitaxel must undergo premedication. Its essence is that in order to prevent a severe hypersensitivity reaction, antihistamines and glucocorticosteroid drugs, antagonists of H2 histamine receptors, are used. An example of this is that dexamethasone is administered in a dose of 20 milligrams from 12 to 6 hours before the infusion. An alternative to dexamethasone can be diphenhydramine (50 mg), or another drug with a similar effect. And also from 30 minutes to one hour - intravenous ranitidine 50 mg. or cimetidine in a quantity of 300 milligrams.

The infusion solution is prepared before the actual start of Paclitaxel administration.

For this purpose, the concentrate is combined with a 0.9% sodium chloride solution. A 5% dextrose solution, dextrose in a solution with sodium chloride for injections, and in addition, Ringer's solution with a 5% dextrose solution, the final concentration of which should be 0.3-1.2 mg/ml, are also allowed in combination with the drug.

Paclitaxel is administered by intravenous infusion, in which the drug in a single dose of 135-175 mg/m2 should enter the body over a period of 3 to 24 hours. Each course is separated from the previous one by a break of at least 21 days. The drug is used until the neutrophil and blood counts are at least 1500/mcl, and platelets, respectively, 100,000/mcl.

Treatment of Kaposi's sarcoma in AIDS with this drug occurs through its administration at 100 mg/m2 over 3 hours with 14-day breaks.

The method of administration and dosage of this antitumor agent may vary based on the medical history, nature of the disease, stage and severity of each individual patient, and factors of individual tolerance to the components of Paclitaxel.

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Use Paclitaxel during pregnancy

The use of Paclitaxel during pregnancy should raise concerns at least due to the fact that, despite the proven effectiveness of the drug as a means of helping to cure many forms of cancer, at present all its mechanisms in the human body have not been fully studied. And for a woman in a position when her body is especially vulnerable, any threat from external influences takes on a significance raised to the nth power. The same statement is true for the future little person for whom she is responsible.

This medication, based on the existing criteria for assessing the possible effect on the child during its intrauterine development (FDA), is assigned category D. This means that, despite the confirmed existence of a risk to the fetus, under a certain combination of factors and circumstances, Paclitaxel may be justified. The drug is prescribed only when the question is about the life and death of a woman expecting a baby or if there is a high probability that the expected positive changes for her, to the least possible extent, may have negative consequences for the fetus.

Since the drug has experimentally confirmed fetotoxic and embryotoxic properties, the use of Paclitaxel during pregnancy is prescribed only in exceptional cases. A woman during treatment with it should use reliable methods of contraception, and during lactation, breastfeeding of the baby should be stopped for the entire duration of the treatment course.

Contraindications

Contraindications to the use of Paclitaxel may be caused, first of all, by individual hypersensitivity both to this drug and to those medications in the dosage form of which there is the presence of macrogolglycerol ricinoleate.

Paclitaxel is included in the list of drugs that should be excluded from the treatment regimen for Kaposi's sarcoma, which may occur in AIDS, if the neutrophil counts recorded during treatment are not greater than 1000/μl.

Another thing to note regarding the initial amount of neutrophils present is that if they do not reach 1500/μl in solid tumors, this fact places the drug in the category of unacceptable for use in treatment.

Paclitaxel may be used with all possible precautions if thrombocytopenia is less than 100,000/μl. If its quantitative indicator is below the lower limit of 1500/μl, the drug is definitely contraindicated.

It is prohibited in cases of liver failure, severe cardiac ischemia, arrhythmia, and a history of myocardial infarction less than six months ago.

It is also recommended to refrain from using Paclitaxel during pregnancy, lactation and breastfeeding.

There are also some cases that are not direct contraindications, but require increased attention during the use of Paclitaxel. These are chronic heart failure, angina, heart rhythm disorders. This also includes a number of infectious diseases.

Like any other medication, Paclitaxel has its strengths and weaknesses, exhibiting an aggressive radical effect, which is what distinguishes many of the drugs used in anti-cancer therapy. But at the same time, the price for the effectiveness achieved in this way is often all sorts of adverse side effects. Therefore, there are contraindications to the use of Paclitaxel and special instructions aimed at preventing and reducing the possibility of all kinds of accompanying negative phenomena.

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Side effects Paclitaxel

The frequency and severity of Paclitaxel side effects are largely determined by the fact that they are dose-dependent.

During the first hours after the drug has been administered, an allergic reaction may develop, such as bronchospasm, decreased blood pressure, flushing of the face, chest pain, and skin rash.

Those organs in the human body that participate in processes related to the performance of the hematopoietic function may show their specific reaction to the use of the drug in the form of developing anemia, thrombocytopenia and neutropenia. The main factor due to which it is necessary to limit the increase in dosage is that the use of increased doses suppresses bone marrow function, which, with its toxic effect, especially affects the granulocytic germ. The level of neutrophils reaches its lowest point in the time period from the 8th to the 11th day, with subsequent normalization after a three-week period.

Characteristic symptoms during the course of treatment with Paclitaxel are inherent to the cardiovascular system. Side effects are displayed as the appearance of unfavorable dynamics of changes occurring with arterial pressure, mainly with a tendency to its decrease. An increase in blood pressure is noted in fewer cases. The result of the drug administration can be the occurrence of increased heart rate, bradycardia, the phenomenon of atrioventricular block, the development of vascular thrombosis and thrombophlebitis. Changes in heart rate indicators on the electrocardiogram are noted.

Due to the active action of the drug in the body, the central nervous system is attacked by it. This mainly occurs as the appearance of paresthesia. Rarely, there are cases of seizures of the grand mal type, the development of ataxia, encephalopathy, visual impairment, and autonomic neuropathy are noted. The latter, in turn, often acts as a cause of paralytic intestinal obstruction and orthostatic hypotension.

Paclitaxel may adversely affect liver function, resulting in increased serum liver transaminases (mainly AST), alkaline phosphatase, and bilirubin. Hepatic encephalopathy and hepatonecrosis may occur.

The respiratory system responds to the drug's action with pulmonary fibrosis, interstitial pneumonia, and the occurrence of pulmonary embolism. When Paclitaxel is used simultaneously with radiation therapy, there is an increased risk that radiation pneumonitis may develop.

The resulting dysfunctions of the digestive system are reflected in the appearance of nausea, vomiting, diarrhea, constipation, and the development of anorexia.

The musculoskeletal system may also be affected by side effects, which manifests itself in myalgia and arthralgia.

Side effects of Paclitaxel can affect various organs and systems of the body and have quite serious consequences. Therefore, it is very important that the drug is used under medical supervision and with careful adherence to a carefully selected dosage, which will lead to the maximum possible positive result and at the same time have the least negative impact on the patient's condition.

Overdose

To determine the optimal regimen and required doses of Paclitaxel for each specific patient, information contained in special medical reference literature is used. The task of the medical specialist in this regard is to select the minimum possible dosage, which contributes to achieving positive progress in healing and at the same time prevent the occurrence of negative consequences that may occur if the required optimal amount of the drug is exceeded.

In case of administration of unreasonably high doses, an overdose is characterized by a certain list of symptomatic manifestations.

When the drug enters the human body in excessive quantities, it causes a significant decrease in the activity of processes associated with the hematopoietic function of the bone marrow.

The central nervous system is also affected, and its response is the development of peripheral neuropathy.

The occurrence of mucositis is observed, in which inflammatory processes develop in the mucous membranes of various internal organs, and their ulceration also occurs.

To avoid such negative consequences of overdose, the patient's condition should be constantly monitored by a physician throughout the entire period of treatment in which Paclitaxel is used. Particular attention should be paid to the number of neutrophils in the blood. If their values are lower than 500/mm3 for more than one week, or if peripheral neutropenia is severe, subsequent courses should be carried out with a 20% reduction in doses.

Overdose of Paclitaxel does not require any specific treatment, the nature of all treatment measures is symptomatic. There is currently no antidote to the drug.

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Interactions with other drugs

Based on studies of the interaction of Paclitaxel with other drugs, it can be stated that when Paclitaxel and cisplatin are administered one after the other, the myelotoxic effect is more pronounced when they are infused in sequence - first cisplatin, followed by Paclitaxel. The total clearance of the latter in this regard was distinguished by an approximately 20% decrease in average values.

When cimetidine was pre-administered prior to drug infusion, mean total paclitaxel clearance was unchanged.

In vivo and in vitro data may indicate that the metabolic processes of Paclitaxel are suppressed in combination with drugs that inhibit microsomal oxidation, namely: verapamil, diazepam, ketoconazole, quinidine, cyclosporine, cimetidine, etc.

In cases where the use of the drug is accompanied by the simultaneous inclusion of dexamethasone, ranitidine, and diphenhydramine in the treatment regimen, this does not in any way affect its binding to proteins in the blood plasma.

Interactions Paclitaxel with other drugs, depending on the combinations formed, can either enhance or reduce the severity of certain aspects of its use. In some cases, this can contribute to achieving a better therapeutic effect of the drug, and in others, lead to a decrease in the effectiveness of its use. All these factors must be taken into account when drawing up a rational treatment plan.

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Storage conditions

The drug is a potent drug and therefore, according to the criteria for special conditions in which medicines must be stored, it belongs to group B. This means that the storage conditions for Paclitaxel primarily require special precautions and that it must be stored separately from all other pharmaceutical products.

It is impossible to ignore such a specific feature as the fact that some of the components included in the composition of Paclitaxel can cause the extraction of di-2-hexyl phthalate (DEHP) from plasticized containers made of polyvinyl chloride. And the longer the drug is stored in such a container, the more its concentration in the solution increases, and accordingly, DEHP is washed out with an ever-increasing degree. Based on this, both for storing and using for the administration of the drug, it is necessary to use equipment that did not use polyvinyl chloride.

The storage conditions for Paclitaxel are otherwise basically not much different from the basic rules and principles that must be followed when dealing with many drugs. This primarily concerns the need to ensure the appropriate temperature (in this case, 25 degrees Celsius) and to exclude exposure to light. It is also traditional to recommend storing drugs where they cannot fall into the hands of children.

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Shelf life

The shelf life of the drug is 2 years from the date of manufacture indicated on the package. Paclitaxel should not be used after the expiration date.