Doxtored (docetaxel) concentracted solution for infusions 20 mg/ml. 1ml. (20 mg.) vial №1

Description

Doxtored Composition
active substance: docetaxel;

1 ml of concentrate contains 20 mg of docetaxel;

Doxtored excipients: polysorbate 80, povidone, citric acid, ethanol.

Doxtored Dosage form
Concentrate for preparation of solution for infusion.

Basic physical and chemical properties: transparent, oily, pale yellow solution.

Doxtored Pharmacotherapeutic group
Antineoplastic drugs. Taxanes. ATX code L01C D02.

Doxtored Pharmacodynamics
Mechanism of action

Docetaxel is an antineoplastic drug, the mechanism of action of which is based on the fact that the drug promotes the accumulation of tubulin in the microtubules of cells and prevents their breakdown, which leads to a significant decrease in the level of free tubulin. Binding of docetaxel to microtubules does not alter the number of protofilaments.

In vitro studies have shown that docetaxel disrupts the microtubular network, which plays an important role in the implementation of vital cell functions both during mitosis and in interphase.

Pharmacodynamic effects

An in vitro clonogenic assay has shown the cytotoxicity of docetaxel against a variety of murine and human tumor cell lines, as well as against cells from only remote human tumors. Docetaxel reaches significant concentrations in the extracellular fluid and ensures a long cell life. In addition, docetaxel is active against some (although not all) cell lines in which the expression of the p-glycoprotein encoded by the drug multidrug resistance gene takes place. In in vivo studies, it turned out that the effect of docetaxel does not depend on the mode of use and is manifested in experiments by a wide range of antitumor activity types in common tumors – both experimental tumors of mice and grafted human tumors.

Pharmacokinetics
Absorption

The pharmacokinetics of docetaxel was studied in phase I studies in patients with cancer after administration of 20-115 mg / m2 of the drug. The pharmacokinetic profile of docetaxel is independent of dose and corresponds to a three-chamber pharmacokinetic model with elimination half-lives for the α-, β- and γ-phases of 4 minutes, 36 minutes and 11.1 hours, respectively. This duration of this indicator in the last phase is partly due to the relatively slow outflow from the peripheral chamber.

Distribution

After taking 100 mg / m2, which was infused over 1 hour, the average peak plasma concentration – 3.7 μg / ml – was obtained from the corresponding AUC of 4.6 μg / ml / hour. The average values ​​of the total clearance and the equilibrium volume of distribution of the drug were 21 l / m2 / year and 113 l, respectively. Interindividual differences in total clearance reached 50%. Docetaxel binds to plasma proteins by more than 95%.

Withdrawal

A study using the radioisotope 14C-docetaxel was conducted with the participation of three patients with cancer. After the oxidative metabolism of the tert-butyl ether group under the action of cytochrome P450, docetaxel was excreted both in the urine and in the feces within 7 days, the excretion in the urine was 6%, with the feces – 75% of the amount of the administered radioisotope. About 80% of the isotope that was in the feces was excreted during the first 48 hours as one main inactive metabolite of three minor metabolites and a very small amount of the drug in unchanged form.

Special patient groups

Age and gender

A population analysis of the pharmacokinetics of docetaxel was performed in 577 patients. The pharmacokinetic parameters assessed using this model were very similar to those obtained in the phase I studies. The pharmacokinetics of the drug was not influenced by either the age or gender of the patients.

Liver dysfunction

In a small number of patients (n = 23), in which, according to clinical biochemical studies, there were mild or moderate liver dysfunctions (an increase in ALT, AST levels ≥1.5 times from the upper limit of normal (upper limit of normal) in combination with an increase in the level of alkaline phosphatase ≥ 2.5 times the upper limit of normal), the total clearance was reduced by an average of 27%.

Fluid retention in the body

The clearance of docetaxel in patients with mild to moderate fluid retention did not change, and there are no data on clearance in patients with severe fluid retention.

Combination therapy

Doxorubicin

When used in combination with other drugs, docetaxel did not affect the clearance of doxorubicin and the level of doxorubicin (and its metabolites) in blood plasma. The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide did not change with their simultaneous use.

Capecitabine

A phase I clinical study on the effect of capecitabine on the pharmacokinetics of docetaxel and vice versa revealed neither the effect of capecitabine on the pharmacokinetics of docetaxel (Cmax and AUC), nor the effect of docetaxel on the pharmacokinetics of the corresponding metabolite of capecitabine 5′-DFUR (5′-deoxy-5-fluorouridine).

Indications
Mammary cancer

Docetaxel in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with:

operable breast cancer with lymph node involvement;
operable breast cancer without affecting the lymph nodes.
In patients with resectable breast cancer without lymph node involvement, adjuvant therapy should be limited if patients are to be treated with chemotherapy according to internationally accepted criteria for primary therapy for early-stage breast cancer.

Contraindications
Docetaxel is contraindicated in patients with a history of severe hypersensitivity reactions to docetaxel or polysorbate 80; patients with an indicator of the number of neutrophils less than 1500 / mm 3; patients with severe liver dysfunction.

Contraindications for other medicines should be considered when combined with docetaxel.