Zolinza

Zolinza is an antineoplastic drug.

Indications Zolinza

It is used for the treatment of cutaneous T-cell lymphoma (progressive or recurrent form). Treatment with the drug is carried out without reference to parallel general chemotherapy.

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Release form

The medicine is released in capsules, 120 pieces in a polyethylene bottle. There is 1 such bottle in a pack.

Pharmacodynamics

Vorinostat is a substance that effectively inhibits histone deacetylases (such as HDAC1, as well as HDAC2 with HDAC3 (category I) and HDAC6 (category II)) (PC50 values are <86 nmol). These enzymes catalyze the process of cleavage of acyl elements from lysine residues of proteins, including transcription factors and histones.

The antitumor effect of vorinostat develops by suppressing the activity of the HDAC component and further accumulation of acetylated proteins, including histones. The process of histone acetylation provokes transcriptional gene activation (this includes genes that have a suppressive effect on tumors), while their expression promotes cellular differentiation or apoptosis, as well as inhibition of tumor growth. At the same time, the vorinostat indicators required for the accumulation of acetylated histones help stop the cell cycle, as well as apoptosis or differentiation of modified cells.

In cell cultures, the substance causes apoptosis of many types of modified tumor cells. In tumor cell cultures, the drug has shown synergistic or additive effects when combined with other types of antitumor treatment, including radiation therapy sessions, as well as the use of cytotoxic drugs, drugs that slow down kinase activity, and cell differentiation inducers.

In vivo, vorinostat exhibits antitumor activity in a relatively broad range of rodent cancer models. These include xenograft models of malignant neoplasms in the human mammary glands and prostate with colon.

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Pharmacokinetics

Suction.

The pharmacokinetic properties of the drug were studied in 23 patients with a widespread form of cancer that was refractory or recurrent.

With a single use of the drug in a 0.4 g portion (together with fatty foods), the average value (± standard AUC value) of serum Cmax of the drug is, respectively, 5.5±1.8 μmol/hour and 1.2±0.62 μmol, and its Tmax level reaches 4 (within 2-10) hours.

With a single dose of 0.4 g on an empty stomach, the average AUC and Cmax reach 4.2±1.9 μmol/hour, as well as 1.2±0.35 μmol, and the average Tmax level is 1.5 (within 0.5-10) hours.

This allows us to conclude that the use of the drug together with fatty foods leads to a 33% increase in the duration of its absorption, as well as a slight decrease in its speed (the Tmax indicator is recorded 2.5 hours later) compared to the use of Zolinza on an empty stomach. During clinical tests in people with cutaneous T-cell lymphomas, vorinostat was taken with food.

Multiple oral administration of the drug (0.4 g dose) with food resulted in average steady-state AUC and Cmax values of 6.0±2.0 μmol/hour and 1.2±0.53 μmol, respectively, and in addition to this, an average Tmax level of 4 (range 0.5-14) hours.

Distribution processes.

In the spectrum of plasma indices of 0.5-50 mcg/ml, about 71% of the substance is synthesized with proteins inside the blood plasma. Vorinostat penetrates the placenta at high speed (in rats and rabbits - when using daily doses equal to 15 and 150 mg/kg, respectively). In this case, transplacental equilibrium is achieved approximately half an hour after administration.

Exchange processes.

Among the main pathways of metabolic transformations of the drug are glucuronidation processes, as well as hydrolysis with subsequent β-oxidation. In human blood serum, the indices of two decay products were measured: O-glucuronide of vorinostat with 4-analino-4-oxobutanoic acid. Both elements have no medicinal activity.

Compared with the vorinostatin element, the equilibrium exposure of the 2 products of drug metabolism is higher than the analogous indicator of vorinostat, respectively, by 4 (vorinostat O-glucuronide) and 13 (4-analino-4-oxobutanoic acid) times.

In vitro tests on human liver microsomes show that the drug is poorly biotransformed by enzymes of the hemoprotein P450 (CYP) system.

Excretion.

Vorinostat is mainly excreted during metabolism, and only less than 1% of the dose is excreted unchanged in the urine. This allows us to determine that renal excretion plays almost no role in the processes of drug elimination from the body.

Equilibrium values in urine have 2 therapeutically inactive products of drug metabolism - vorinostat proglucuronide (16±5.8% of the portion) and 4-analino-4-oxobutanoic acid (36±8.6% of the portion). The total excretion of the active component and its 2 decay products is on average equal to 52±13.3% of the Zolinza dosage.

The half-life of the active ingredient of the drug and the O-glucuronide metabolite is about 2 hours, and the half-life of 4-analino-4-oxobutanoic acid is approximately 11 hours.

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Dosing and administration

The medication is taken orally, with food. The recommended serving size is 0.4 g (equivalent to 4 capsules), taken once a day. If necessary, the dosage can be reduced to 3 capsules (0.3 g of the substance), which are also taken once a day. The dosage regimen can be reduced to 5 consecutive days per week.

Therapy is carried out until all symptoms of pathology progression completely disappear or signs of toxicity appear.

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Use Zolinza during pregnancy

Adequate and properly controlled tests regarding the use of Zolinza during pregnancy have not been performed. Women of reproductive age are advised to refrain from planning to conceive during the period of therapy. If there is a need to take the medicine during pregnancy or if pregnancy occurs during therapy, the patient should be informed that the treatment may potentially have a negative effect on the fetus.

There is no data on whether the drug can pass into breast milk. Because many drugs are excreted in breast milk, and there is a risk of serious side effects in the infant, it is recommended to stop breastfeeding during therapy.

Contraindications

Main contraindications:

• severe hypersensitivity to any component of the drug;
• a disorder in the functioning of the liver that has a severe form of expression.

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Side effects Zolinza

A single use of 0.4 g of the substance per day leads to the appearance of the following side effects:

• gastrointestinal dysfunction: nausea, constipation, weight loss, diarrhea, loss of appetite, vomiting and anorexia;
• General symptoms: chills and feeling of weakness;
• disorders of hematopoiesis: anemia or thrombocytopenia;
• taste disturbances: dryness of the oral mucosa or dysgeusia.

In addition to the above-described violations, the following negative symptoms are also quite common (after a single use of 0.4 g of the drug per day):

• epidermal lesions: development of alopecia;
• disorders affecting the musculoskeletal system: muscle spasms;
• laboratory test results: increased blood creatinine levels.

People taking the drug in different doses had generally similar adverse symptom profiles:

• infectious or invasive signs: occasionally, bacteremia of streptococcal origin developed;
• disorders of nutritional and metabolic processes: dehydration was often noted;
• vascular dysfunction: sometimes blood pressure readings dropped or deep vein thrombosis developed;
• problems with respiratory activity: embolism in the pulmonary vessels was often noted;
• signs affecting the gastrointestinal tract: bleeding inside the gastrointestinal tract was sometimes noted;
• disorders of the hepatobiliary tract: ischemia in the liver area was occasionally observed;
• problems with the functioning of the nervous system: fainting or ischemic stroke were sometimes recorded;
• systemic manifestations: sometimes there was pain inside the sternum or an increase in temperature, and also, for an unknown reason, death occurred.

Overdose

There are no specific data regarding therapy for Zolinza intoxication.

The following daily doses were tested in clinical trials: 0.6 g (once a day), 0.8 g (2 times a day for 0.4 g) and 0.9 g (3 times a day for 0.3 g). No adverse reactions were observed in 4 people who took a dose higher than the recommended dose (but not the highest dose tested).

The therapeutic effect of the drug may develop even after the medicinal element ceases to be determined in the blood serum. There is no data on the degree of excretion of the substance during dialysis.

In case of overdose, it is necessary to carry out the usual supportive measures: remove unabsorbed medicine from the gastrointestinal tract, and then monitor the functioning of important organs and systems, and prescribe (if necessary) supportive procedures.

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Interactions with other drugs

Coumarin derivatives together with anticoagulants.

Combining coumarin forms of anticoagulants with the drug leads to an increase in PT values, as well as an increase in the INR level. If therapy with the simultaneous use of Zolinza and coumarin derivatives is required, INR and PT values should be regularly monitored during the entire period of therapy.

Other drugs that inhibit the activity of histone deacetylases.

It is prohibited to combine the drug with other drugs with a similar effect (for example, with valproic acid), because this may potentiate the severity of negative symptoms characteristic of this category of drugs.

The combined use of Zolinza and valproic acid resulted in the development of severe thrombocytopenia (grade 4) in patients, as well as anemia and bleeding within the gastrointestinal tract.

Other medications.

Vorinostat inhibits microsomal isoenzymes within the CYP hemoprotein system, which participate in the metabolic processes of other drugs, only when used in high concentrations (PC50 level >75 μmol). During the study of gene expression in human hepatocytes, the potential for vorinostat to inhibit the activity of CYP2C9 isoenzymes, as well as CYP3A4, was discovered, but at values ≥10 μmol - exceeding therapeutically significant ones.

Therefore, in clinical practice, the effect of the drug on the pharmacokinetic characteristics of other medications is not expected. Since the isoenzymes of the CYP hemoprotein system are not participants in the metabolic transformations of drugs, the development of interactions with other drugs is not expected when Zolinza is taken in combination with substances that suppress or induce enzymes of the CYP hemoprotein system.

However, it should be taken into account that the corresponding clinical tests studying the interactions of other drugs and vorinostat have not been performed.

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Storage conditions

Zolinza should be kept in a place out of reach of small children. Temperature indicators should not exceed 30°C.

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Shelf life

Zolinza can be used within 24 months from the date of release of the therapeutic drug.

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Application for children

There is no information about the possible effectiveness and safety of the drug in children, which is why it is not used in pediatrics.

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Analogues

An analogue of the drug is Vorinostat.

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