Vero-fludarabine

Vero-fludarabine is an antineoplastic drug that is a structural purine analogue. The drug contains fludarabine phosphate. This is a fluorinated nucleotide analogue of the antiviral substance vidarabine (element 9-β-D-ara-A), which has relative resistance to deamination of the ADA component.

Inside the human body, the active element of the drug is dephosphorylated at high speed to form 2-fluoro-ara-A, which is absorbed by cells. It is then phosphorylated intracellularly by deoxycytidine kinase relative to the active 3-phosphate (element 2-fluoro-ara-ATP).

Indications Vero-fludarabine

It is used for chronic B-cell lymphocytic leukemia, as well as for low-grade NHL.

Release form

The component is released in the form of injection powder for intravenous injections. The lyophilisate contains 50 mg of the active ingredient and is sold in glass vials.

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Pharmacodynamics

This metabolic component slows down DNA polymerase with ribonucleotide reductase, and in addition, α-, δ- with ε-DNA primase, as well as DNA ligase, which as a result leads to a slowdown in DNA binding. Along with this, a partial slowdown of RNA polymerase 2 occurs, and, as a result, a decrease in protein binding.

There is no confirmed information regarding a clear relationship between the pharmacokinetic parameters of 2-fluoro-ara-A and the effectiveness of oncological therapy. However, changes in hematocrit values and the appearance of neutropenia confirm dose-dependent suppression of hematopoiesis due to the cytotoxic properties of fludarabine phosphate.

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Pharmacokinetics

Fludarabine is a water-soluble prodrug (2-fluoro-ara-A) that is rapidly dephosphorylated in the human body to form a nucleoside (2-fluoro-ara-A). Intraplasmic protein binding is weak.

With a single infusion of the element 2-fluoro-ara-AMP in a portion of 25 mg/m2 ^to persons with CLL for half an hour, plasma Cmax values of 2F-ara-A are equal to 3.5-3.7 μm by the end of the infusion procedure. The corresponding values of 2-fluoro-ara-A after the 5th portion moderately accumulate; the average Cmax values by the end of the infusion are equal to 4.4-4.8 μm. With therapy according to a 5-day regimen, low plasma values of 2-fluoro-ara-A increase approximately twofold. Accumulation of 2F-ara-A does not develop after several treatment courses.

Postmaximal values decrease over a period of 3 pharmacokinetic phases with an initial half-life of approximately 5 minutes. The intermediate half-life is approximately 1-2 hours; the final half-life is approximately 20 hours.

Excretion of 2-fluoro-ara-A is realized mainly through the kidneys. 40-60% of the dose applied via intravenous injection is excreted in the urine.

In people with weakened kidney function, the systemic clearance rate is reduced, which is why the drug dosage must be reduced.

The 2-fluoro-ara-A component actively moves into leukemic cells, undergoing rephosphorylation there into monophosphate, and then into 2- and 3-phosphate. The latter is the main intracellular metabolic element (it is the only one with a cytotoxic effect).

The Cmax values of 2-fluoro-ara-ATP inside the altered lymphocytes of people with CLL are on average noted after 4 hours and are characterized by significant personal variability. The 2-fluoro-ara-ATP values inside leukemic cells constantly significantly exceed the plasma Cmax level of the 2-fluoro-ara-A component, from which one can conclude about the specificity of the accumulation that occurs.

The excretion of 2-fluoro-ara-ATP from target cell sites is realized with an average half-life of 15 and 23 hours.

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Dosing and administration

The medication is administered intravenously through a drip for half an hour. The therapy is performed under the supervision of an experienced and qualified physician who has previously performed antitumor treatment.

It is necessary to use 25 mg/m2 ^of the medicine - every day for 5 days; such courses should be carried out with 28-day intervals. The lyophilisate from the vials is diluted in injection water (2 ml). Each 1 ml of the resulting liquid contains 25 mg of the fludarabine phosphate component.

The required dose (calculated based on the size of the human body surface) is drawn into a syringe. For bolus injections, this medicinal dose is dissolved in 0.9% NaCl (10 ml). To perform an infusion, the dose drawn into the syringe should be diluted in 0.1 l of the above solution.

The duration of the therapeutic cycle is determined by the effectiveness of treatment and the development of tolerance to Vero-Fludarabine.

People with CLL need to use the drug until the maximum response is achieved (partial or complete remission is observed after 6 courses). After this, the use of the drug is discontinued.

People with low-grade NHL require continued therapy until the maximum response (partial or full remission) is achieved. When the desired effect is achieved, the option of performing 2 more courses of consolidated treatment is considered. In clinical trials of people with the above pathology, most underwent a maximum of 8 treatment courses.

Patients with renal dysfunction need to adjust the dosage of the drug. At the level of CC in the range of 30-70 ml per minute, the portion is reduced to 50%. To assess the toxicity indicators, careful hematological monitoring should be performed.

Vero-Fludarabine should not be prescribed if the creatinine clearance values are below 30 ml per minute.

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Use Vero-fludarabine during pregnancy

The medication is not prescribed during pregnancy or breastfeeding.

Contraindications

Main contraindications:

• strong personal sensitivity to the drug and its components;
• renal dysfunction (creatinine clearance values below 30 ml per minute);
• hemolytic anemia in the decompensated phase.

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Side effects Vero-fludarabine

Among the main side effects:

• damage to the hematopoietic organs: thrombocyto- or neutropenia, as well as anemia. The number of neutrophils decreases maximally on average on the 13th day (within the range of 3-25 days) from the start of therapy, and platelets - on the 16th day (in the range of 2-32 days). In this case, myelosuppression can be of high intensity and cumulative. A decrease in the number of T-lymphocytes, noted in the case of prolonged use of fludarabine, can increase the likelihood of opportunistic infections, including latent viral lesions developing due to reactivation (for example, a multifocal form of leukoencephalopathy, which has a progressive nature);
• metabolic disorders: due to neoplasm lysis, hyperphosphatemia, -kalemia or -uricemia may occur, as well as hypocalcemia, metabolic acidosis, urate crystalluria, hematuria and renal dysfunction. The first symptom of neoplasm lysis is hematuria and the appearance of acute pain;
• damage to the function of the PNS and CNS: polyneuropathy. Rarely, agitation or coma is observed, as well as confusion and epileptiform seizures;
• problems with the functioning of the sense organs: development of neuritis affecting the optic nerve, visual impairment or neuropathy, as well as blindness;
• respiratory system infections: pneumonia develops. Rarely, pneumonitis, pulmonary infiltration or pulmonary fibrosis occurs, which causes cough and dyspnea;
• digestive disorders: anorexia, stomatitis, nausea, diarrhea or vomiting. Occasionally, thrombocytopenia can cause bleeding in the gastrointestinal tract, and the activity of pancreatic and liver enzymes increases;
• disorders of the cardiovascular system function: arrhythmia or cardiovascular failure are occasionally observed;
• problems with the functioning of the urogenital tract: hemorrhagic cystitis occasionally occurs;
• lesions of subcutaneous tissues with epidermis: rashes. Occasionally, TEN or SSD appears;
• autoimmune manifestations: regardless of the presence or absence of a history of autoimmune processes, and in addition to the Coombs test data, there are reports of the occurrence of a threat to life, and in some cases the development of life-threatening autoimmune manifestations (autoimmune types of thrombocytopenia or anemia of a hemolytic nature, pemphigus, thrombocytopenic purpura and Evans syndrome) during therapy with fludarabine or after its completion;
• other symptoms: chills, malaise, fever and severe fatigue, infections, weakness, as well as peripheral edema (are typical signs).

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Overdose

When Vero-Fludarabine is administered in too high doses, it causes incurable damage to the central nervous system, leading to blindness and coma. Severe thrombocyto- and neutropenia are also observed.

There is no antidote. It is necessary to discontinue the drug and perform symptomatic procedures.

Interactions with other drugs

The use of fludarabine in combination with the substance pentostatin in the treatment of refractory CLL often causes death (because this combination has a high degree of toxicity to the lungs). For this reason, prescribing these drugs together is prohibited.

The medicinal efficacy of fludarabine may be reduced by the administration of dipyridamole or other adenosine reuptake inhibitors.

Vero-Fludarabine intravenous fluid must not be mixed with other medications.

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Storage conditions

Vero-Fludarabine should be stored in a dark place, out of reach of children and moisture. Temperature values are within the limits of 25°C.

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Shelf life

Vero-Fludarabine is approved for use for a 2-year period from the date of manufacture of the medication.

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Application for children

The safety and efficacy of fludarabine in pediatric patients have not been studied.

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Analogues

The analogs of the drug are Darbines, Flutothera, Flidarin with Fludarabel, Flugarda and Fludarabine with Fludara.

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