Zoliza

Zolinza is an antineoplastic drug.

Indications Zoliza

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

[1], [2]

Release form

The drug is produced in capsules, 120 pieces inside a polyethylene bottle. In a pack - 1 such a bottle.

Pharmacodynamics

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

The antitumor effect of vorinostat develops by suppressing the activity of the HDAC component and further cumulating acetylated proteins, among which are histones. The process of acetylation of histones provokes transcriptional gene activation (this includes genes that exert a suppressive effect on tumors), while their expression promotes cellular differentiation, either apoptosis or suppression of tumor growth. Along with this, the parameters of vorinostat required for the accumulation of acetylated histones help to stop the cell cycle, and in addition apoptosis or differentiation of the modified cells.

Within the cell cultures, the substance causes apoptosis of many types of mutated tumor cells. Inside the cell cultures of the neoplasms, the drug showed a synergistic or additional effect when combined with other types of antitumor treatment, among which radiotherapy sessions, as well as the use of cytotoxic drugs, drugs slowing the activity of kinases, and inducers of cellular differentiation.

In vivo, vorinostat shows the antitumor effect of a relatively wide range of cancer models in rodents. Among such models are xenografts of neoplasms of malignant nature in the area of human mammary glands and prostate with large intestine.

[3], [4], [5]

Pharmacokinetics

Suction.

Pharmacokinetic properties of the drug were studied in 23 patients with a common form of cancer, which has a refractory or recurrent character.

With a single use of medicines in a 0.4 g portion (along with fatty dishes), the mean (± standard AUC) of the serum Cmax of the medicament is 5.5 ± 1.8 μmol / h, respectively, and 1.2 ± 0.6 μmol , and the level of its Tmax reaches 4 (within 2-10) hours.

With a single use of 0.4 g dose on an empty stomach, the average AUC and Cmax value is 4.2 ± 1.9 μmol / h, and 1.2 ± 0.35 μmol, and the mean Tmax is 1.5 (within the 0, 5-10) hours.

This allows us to conclude that the use of medicines together with fatty dishes leads to an increase of 33% in the duration of its absorption, as well as a slight decrease in its speed (the Tmax index is recorded 2.5 hours later) compared with the use of fasting Zolinz. During clinical tests, in people with skin T-cell type lymphoma, the vorinostat was taken with food.

Reusable ingestion of the medication (0.4 g portion) together with food resulted in the average equilibrium AUC and Cmax values reaching, respectively, 6.0 ± 2.0 μmol / h, and 1.2 ± 0.53 μmol, and in addition to this, the average Tmax level, equal to the 4th (within the range of 0.5-14) hours.

Distribution processes.

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

Exchange processes.

Among the main ways of metabolic transformation drugs - the processes of glucuronization, as well as hydrolysis with further β-oxidation. Within the human blood serum, the parameters of two decay products were measured: o-glucuronide vorinostate with 4-analano-4-oxobutanoic acid. Both elements have no drug activity.

In comparison with the element of vorinostatin, the equilibrium exposure of 2 products of drug metabolism is higher than that of the vorinostat, respectively, in 4 (O-glucuronide vorinostat) and 13 (4-analano-4-oxobutanoic acid) times.

In vitro tests performed on human hepatic microsomes show that the drug is poorly biotransformed under the influence of P450 (CYP) hemoprotein system enzymes.

Excretion.

The vorinostat is mainly excreted during metabolism, and only less than 1% of the dosage is excreted unchanged together with the urine. This allows us to determine that excretion through the kidneys plays almost no role in the processes of excretion of drugs from the body.

The equilibrium values within the urine have 2 therapeutically inactive metabolites of the drug, vorinostat proglucuronide (16 ± 5.8% servings) and 4-analano-4-oxobutanoic acid (36 ± 8.6% servings). The total excretion of the active component and its 2 decay products averaged 52 ± 13.3% of the Zolinz dosage.

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

[6]

Dosing and administration

Medication is consumed orally, along with food. The recommended serving size is 0.4 g (corresponds to 4 capsules), with 1-fold intake per day. If required, the dosage can be reduced to 3 capsules (0.3 g of substance), which also take 1-day for a day. The dosage regimen can be shortened to 5 consecutive days per week.

Therapy is carried out until the moment when all the symptoms of the progression of the pathology completely disappear or there are signs of toxicity.

[8]

Use Zoliza during pregnancy

Adequate and properly controlled tests regarding the use of Zolinz during pregnancy were not performed. Women of reproductive age are recommended to abandon conception planning for the period of therapy. If you need to take drugs during pregnancy or when it comes along during the therapy, the patient needs to be informed that treatment can potentially have a negative effect on the fetus.

There is no evidence as to whether the drug is able to pass into breast milk. Because many drugs are excreted in breast milk, and there is a risk of serious side effects in the baby, it is recommended that you stop breastfeeding during therapy.

Contraindications

The main contraindications:

• strong sensitivity to any element of the drug;
• a disorder in the work of the liver, which has a severe form of expression.

[7]

Side effects Zoliza

One-time use of 0.4 g of substance per day leads to the appearance of such side-effects:

• disorders of the gastrointestinal tract: nausea, constipation, weight loss, diarrhea, weakening of appetite, vomiting and anorexia;
• common manifestations: chills and a sense of weakness;
• disorders of hematopoietic activity: anemia or thrombocytopenia;
• taste disorders: dry mouth mucosa or dysgeusia.

In addition to the above-described disorders, often enough negative signs also appear (after a 1-time intake of 0.4 g of drug per day):

• defeat of the epidermis: development of alopecia;
• disorders affecting the musculoskeletal system: muscle spasms;
• laboratory test data: an increase in the blood values of creatinine.

In people taking the medicine in other portions, the profile of negative symptoms was generally similar:

• infectious or invasive signs: the bacteremia of streptococcal origin occasionally developed;
• disorders of nutritional and metabolic processes: often marked dehydration;
• dysfunction of the vascular system: sometimes lower blood pressure or developed thrombosis in the deep veins;
• problems with respiratory activity: often embolism in the pulmonary vessels;
• signs that affect the work of the digestive tract: sometimes there was bleeding in the gastrointestinal tract;
• disturbances in the functioning of the hepatobiliary tract: occasionally there was ischemia in the liver region;
• problems with the work of the National Assembly: sometimes fainting or an ischemic stroke occurred;
• systemic manifestations: sometimes there were painful sensations inside the sternum or an increase in temperature, and, for an unknown reason, death came.

Overdose

There are no specific data on therapy for intoxication with Zolinzoy.

During the clinical tests, daily doses were tested: 0.6 g (once per day), 0.8 g (2 times a day for 0.4 g) and 0.9 g (3 times a day for 0.3 g). In 4 people who used a dosage exceeding the recommended (but not the highest), no negative reactions were noted.

The therapeutic effect of drugs can develop even after the drug element is no longer detected within the blood serum. There is no data on the degree of excretion of the substance in dialysis.

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

[9], [10]

Interactions with other drugs

Coumarin derivatives along with anticoagulants.

Combination of the coumarin forms of anticoagulants with the drug leads to an increase in PTV values, as well as an increase in the level of INR. If therapy is required with the simultaneous use of Zolinz and coumarin derivatives, it is necessary to regularly monitor the indices of MNO and PTV during the entire period of therapy.

Other medications that slow down the activity of histone-deacetylase.

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

Combined use of Zolinase and valproic acid led to the appearance of patients with thrombocytopenia, which is pronounced (grade 4), as well as anemia and bleeding within the gastrointestinal tract.

Remaining medications.

Vorinostat depresses isozymes of microsomes inside the hemoprotein CYP system, which participate in the metabolic processes of other drugs, only when used in high concentrations (PC50> 75 μmol). During the study of gene expression within human hepatocytes, the potential for inhibition of the activity of isoenzymes CYP2C9, as well as CYP3A4, was found to be inhibited by vorinostat, but at values of ≥10 μmol - exceeding therapeutically significant.

Therefore, in clinical practice, the effect of drugs on the pharmacokinetic characteristics of other drugs is not expected. Because the isoenzymes of the CYP hemoprotein system are not participants in the metabolic transformations of drugs, it is also not expected that interactions with other drugs will develop with the combined use of Zolinza with substances that inhibit or induce the enzymes of the CYP hemoprotein system.

But it is necessary to take into account that the corresponding clinical tests with the study of the interactions of other drugs and vorinostat were not performed.

[11], [12]

Storage conditions

Zolens should be kept in a place that is closed from access by small children. Temperature values are not higher than 30 ° C.

[13]

Shelf life

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

[14]

Application for children

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

[15], [16]

Analogues

An analogue of the drug is the drug Vorinostat.

[17], [18], [19], [20]