Exomesin

Exomesin is an enzyme inhibitor, belongs to the category of hormone antagonists, as well as similar drugs.

Indications Exomesin

It is indicated as an adjuvant therapy in the early stages of breast cancer development (with unspecified or positive estrogen receptor test) in postmenopausal patients - to reduce the risk of contralateral, locoregional, and distant metastases.

As a first-line drug in the treatment of advanced breast cancer (with a positive hormone receptor test) in women in the induced or natural postmenopause stage.

As a second-line drug in the treatment of widespread breast cancer in women during induced or natural postmenopause, who have also shown progression of the pathology after the use of monotherapy with antiestrogens.

As a third-line agent for the treatment of advanced breast cancer in postmenopausal women who have also shown disease progression after polyhormonal treatment.

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Release form

It is produced in tablet form. One blister contains 10 tablets, one package contains 3 blister strips.

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Pharmacodynamics

Exemestane is a steroid-type aromatase inhibitor (irreversible form), similar in structure to the natural component androstenedione. During postmenopause, estrogens in the female body are mainly produced by converting androgens into them - under the influence of the aromatase enzyme in peripheral tissues.

Estrogen blockade through aromatase inhibition is an effective, selective hormonal approach to the treatment of postmenopausal breast cancer.

Oral administration of the drug in the postmenopausal stage significantly reduces serum estrogen levels, already with a dosage of 5 mg. The drug achieved peak suppression (> 90%) with dosages of 10-25 mg. As a result of using a daily dosage of 25 mg of the drug in patients with breast cancer, the total activity of the aromatase substance was reduced by 98%.

Exemestane has no estrogenic or progestogenic effect. The weak androgenic effect is most likely due to the 17-hydroderivative and is observed mainly when using the drug in high doses.

As a result of the study of the effect of the drug on the body during its long-term use, no significant effect of the adrenal glands on the process of biosynthesis of aldosterone or cortisol was found. Their level was measured before or after taking a sample with ACTH - this demonstrates the selectivity of the drug relative to other enzymes involved in steroidogenic metabolism. This allows us to abandon HRT using mineralocorticoids and GCS.

A slight increase in the level of FSH, as well as LH in the serum, was observed even when taking small doses. But this effect is expected for this pharmacological category, and is probably a consequence of feedback at the pituitary level. It is due to a decrease in the estrogen level, as a result of which the release of gonadotropins through the pituitary gland is stimulated (during postmenopause, including).

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Pharmacokinetics

After internal use, the drug is rapidly absorbed. Most of the dose is absorbed from the gastrointestinal tract. The bioavailability index in humans is unknown, but there are suggestions that it is limited by a significant first-pass effect in the liver. In animals, this index is 5%.

When taking a single dose of the drug, the peak plasma concentration (18 ng/ml) is reached after 2 hours. It was found that taking it with food accelerates absorption, and the plasma indicator increases by 40% compared to the same level after taking the drug on an empty stomach.

The distribution volume of the drug (without correction for the oral bioavailability index) is 20,000 l. The pharmacokinetics is linear, and the terminal half-life is 24 hours. Synthesis with plasma protein is 90% regardless of the drug concentration. The active component together with decay products is synthesized with erythrocytes.

Repeated use of exemestane does not result in unexpected accumulation of the substance in the body.

The active substance is metabolized by oxidation of the methyl radical at position 6 using the CYP 3A4 isoenzyme, or by reduction of the 17-keto group by aldo-keto reductase with subsequent conjugation. The clearance rate of exemestane is approximately 500 l/h (without possible adjustments for oral bioavailability).

With respect to aromatase inhibition, the breakdown products of exemestane are either completely inactive or less active than the parent compound. Administration of a single dose of 14C-labeled compound showed that the elimination of the drug and its breakdown products generally occurred over about 1 week. The dosage was excreted in equal parts (40% each) in the feces and urine. Approximately 0.1-1% of the radioactive dosage was eliminated unchanged (radioactively labeled substance) in the urine.

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Dosing and administration

The recommended daily dosage is 25 mg (1 tablet). Drink once a day, preferably after meals.

In early breast cancer, treatment should last until the end of 5 years of sequential combination hormonal therapy (tamoxifen, and later exemestane) or less if distant or local metastases or a contralateral tumor appear.

Patients with advanced breast cancer need to take the drug until the cancer progresses noticeably.

For patients with liver or kidney failure, no dosage adjustment is necessary.

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Use Exomesin during pregnancy

There is no clinical data on the use of Exomesin in pregnant women. Animal studies have shown that the drug has reproductive toxicity, which is why its use during pregnancy is prohibited.

Contraindications

Contraindications include: intolerance to the active component or auxiliary elements of the drug, and also the premenopausal period.

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Side effects Exomesin

Overall, the drug was well tolerated during clinical trials (used at the recommended daily dose of 25 mg), and adverse reactions were generally moderate to mild:

• metabolic processes: anorexia often developed;
• mental disorders: mainly insomnia, also quite often the development of depression occurred;
• organs of the nervous system: often – headaches, quite often also – the appearance of dizziness or carpal tunnel syndrome, rarely – a feeling of drowsiness;
• cardiovascular system: hot flashes (very common);
• digestive system organs: nausea is most often observed, but abdominal pain, dyspeptic symptoms, diarrhea, constipation and vomiting may often develop;
• subcutaneous tissue and skin: very often sweating increases, alopecia and skin rash are also quite often observed;
• skeleton and bone system: very often there is pain in the skeletal muscles, as well as joints (development of arthralgia and, less often, osteoarthritis, arthritis, pain in the muscles, limbs or back, and in addition to this, a stiff feeling in the joints), fractures or osteoporosis often occur;
• systemic disorders: mainly the development of fatigue, less often peripheral swelling or pain appears, asthenia develops quite rarely.

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Overdose

Clinical studies have demonstrated good tolerability of the drug after healthy volunteers took a single dose of up to 800 mg, as well as after patients with widespread breast cancer (during menopause) took a dose of up to 600 mg. The size of a single dose of the drug that could lead to the development of symptoms dangerous to health and life is unknown. Death in animals occurred after a single dose administration, respectively, 2000 and 4000 times exceeding the recommended human dose (in terms of dose per mg/m2 ⁾.

The drug has no specific antidote; symptomatic therapy is required in case of overdose. Supportive measures are also required - constant monitoring of the patient, as well as careful monitoring of all vital signs.

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Interactions with other drugs

In vitro testing has shown that the drug is metabolized by hemoprotein 450 (CYP) 3A4 and aldo-keto reductase. The drug is not a blocker of any of the main CYP isoenzymes. Specific inhibition of the CYP 3A4 element by the substance ketoconazole has no noticeable effect on the pharmacokinetic properties of Exomesin.

When studying the interaction with the substance rifampicin (a pronounced inhibitor of the CYP 450 element), it was found that its combination (at a daily dosage of 600 mg) with a single dose of Exomesin reduces the AUC level of the latter by 54%, and the peak concentration indicator by 41%. It is believed that combination with anticonvulsants (for example, carbamazepine or phenytoin), rifampicin, as well as herbal medicines containing St. John's wort (it induces the CYP3A4 element) can reduce the effectiveness of the drug.

Exemestane should be combined with caution with drugs with a small drug range that also metabolize the CYP3A4 element. There is data on clinical experience of combined use of Exomesin and other antitumor drugs.

The drug is prohibited to be combined with drugs containing estrogens, since their combination causes a negative pharmacological effect.

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Storage conditions

Stored under standard conditions for medicinal products, out of reach of small children. Temperature – maximum 25°C.

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Shelf life

Exomesin is suitable for use for 3 years from the date of manufacture of the medicine.

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