Abiraterone - instructions for use, dose, side effects, contraindications

Abiraterone is an inhibitor of androgen biosynthesis. In particular, abiraterone selectively inhibits the activity of the enzyme 17α-hydroxylase / C17,20-lyase (CYP17). This enzyme is necessary for the biosynthesis of androgens in the testes, adrenals and cells of the tumor of the prostate.

CYP17 catalyzes the conversion of pregnenolone and progesterone by 17α-hydroxylation and breaking of the C17,20 bond into testosterone precursors: dehydroepiandrosterone and androstenedione, respectively. The inhibition of CYP17 activity is also accompanied by increased synthesis of mineralocorticoids in the adrenal glands.

Antiandrogenic therapy, such as the use of luliberin agonists or orchidectomy, weakens the synthesis of androgens in the testicles, but does not affect the synthesis of androgens in the adrenal gland and tumor.The use of abiraterone together with lylyberyrin agonists (or orchidectomy) lowers serum testosterone concentrations to below the detection threshold. The concentration of prostate-specific antigen (PSA) serves as a biomarker in patients with prostate cancer.

Pharmacokinetics:

When administered orally, the prodrug of abiraterone acetate is converted to an active metabolite abiraterone, which has anti-androgenic activity. Joint intake with food increases the absorption of the drug and, therefore, can increase and greatly alter the effect of the drug, therefore abiraterone should be taken on an empty stomach. The drug binds well to proteins (> 99%) and is metabolized in the liver with the participation of CYP3A4 and SULT2A1 in inactive metabolites. Abiraterone is excreted with faeces (~ 88%) and urine (~ 5%). The final half-life is 12 ± 5 hours.

Indications:In combination with prednisolone for the treatment of metastatic castration-resistant prostate cancer in patients with progression of the disease during or after chemotherapy involving docetaxel.

ICD-10

II.C76-C80.C79 Secondary malignant neoplasm of other sites

II.C60-C63.C61 Malignant neoplasm of prostate

Contraindications:

severe liver dysfunction;

- children and adolescence under 18;

- hypersensitivity to abiraterone.

Carefully:

- Patients with impaired renal function of a serious degree, because there are no clinical data on the use in this category of patients.

- Patients whose condition may worsen with an increase in blood pressure or the development of hypokalemia, for example, with heart failure, recent myocardial infarction or ventricular arrhythmia; with left ventricular ejection fraction less than 50%, heart failure of III-IV functional class according to NYHA classification;

- Lactase deficiency, lactose intolerance, glucosogalactose malabsorption;

- Patients with excessive production of mineralocorticoids;

- Patients with adrenal insufficiency.

Pregnancy and lactation:

The action category for fetus by FDA is N.

Abiraterone is not suitable for use in women. There are no data on the use of the drug in pregnant women. Abiraterone contraindicated to pregnant women and able to become pregnant women. It is not known whether the drug or its metabolites are excreted in milk.

To prevent accidental exposure, pregnant women or women of childbearing age should not work with abiraterone without gloves.

It is not known whether there is abiraterone or its metabolites in semen. During the treatment it is necessary to use a condom if a sexual intercourse with a pregnant woman is planned. If the sexual act is planned with a woman of childbearing age, it is necessary to use a condom along with other effective methods of contraception.

Dosing and Administration:

Intended for oral administration.

In the combination therapy with prednisone or prednisolone in low doses, the recommended daily dose of abiraterone is 1 g (4 tables of 250 mg) 1 time / day for 1 hour before meals or 2 hours after meals. Abiraterone can not be taken with food. Within 1 hour after taking the drug, eating is not recommended.

If you miss a regular daily dose of abiraterone or prednisolone the next day, you should take the usual dose of the missed drug.

Side effects:

Most often: peripheral edema, hypokalemia, arterial hypertension and urinary tract infections.

From the side of the liver: hepatotoxicity, accompanied by increased activity of ALT, ACT and total bilirubin (the mechanism of hepatotoxicity development is currently unknown).

Infectious diseases: very often - urinary tract infections.

From the endocrine system: infrequent adrenal insufficiency.

From the laboratory indicators: very often - hypokalemia; often hypertriglyceridemia, increased ALT activity.

From the cardiovascular system: very often - arterial hypertension; often - heart failure, incl. acute heart failure, left ventricular failure, reduced left ventricular ejection fraction, angina pectoris, arrhythmia, atrial fibrillation, tachycardia.

From the musculoskeletal system and connective tissue: often - fractures (with the exception of pathological fractures).

From the side of the kidneys and urinary tract: often - hematuria.

Disorders from the gastrointestinal tract: often - indigestion.

Common violations: very often peripheral edema.

Overdose:

Data on an overdose of abiraterone are limited. There is no specific antidote. In case of an overdose, the drug should be discontinued and general supportive measures should be taken, including arrhythmia control. Liver function should also be monitored.

Interaction:

Taking the drug simultaneously with food significantly increases the absorption of abiraterone. The effectiveness and safety of the drug taken with food is not established, so joint intake is unacceptable.

It is recommended to use caution abiraterone in patients receiving drugs that are metabolized with the participation of CYP2D6, especially for drugs with a narrow therapeutic index. In such cases, the possibility of reducing the dose of drugs should be considered, including. dextromethorphan, metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol.

Based on in vitro data abiraterone is a substrate of the CYP3A4 isoenzyme. Caution is necessary when concomitantly taken with strong inhibitors of the isoenzyme CYP3A4 (ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) and inductors (phenytoin, carbamazepine, rifampicin, rifabutin, rifapentin, phenobarbital).

There are no clinical data on the use of abirterone with preparations that are substrates of the isoenzyme CYP2C8 (for example, with paclitaxel and repaglidine).

Special instructions:

Before starting the use of the drug should correct hypokalemia and increase blood pressure. AD, the concentration of potassium in the blood plasma and the degree of fluid retention should be monitored at least 1 time per month.

Before the treatment with abiraterone, every 2 weeks during the first three months of treatment, and then monthly, the activity of serum transaminases and the concentration of bilirubin should be measured. If during the treatment the patients developed signs of hepatotoxicity (increased ALT activity is 5 times higher than IGN or bilirubin concentration 3 times higher than ULN), therapy should be stopped immediately before the liver function is fully normalized. Repeated therapy in patients with normalized liver function can begin with a reduced dose of 500 mg 1 time / day.If symptoms of hepatotoxicity occur at a dose of 500 mg, abiraterone should be discontinued. With the development of a severe form of hepatotoxicity (ALT activity exceeds HHV 20 times) in any period of therapy abiraterone should be canceled, re-application in such cases is impossible.

In patients receiving abiraterone, there may be an increase in blood pressure, hypokalemia and fluid retention due to increased concentration, mineralocorticoids in the blood due to inhibition of CYP17. The introduction of SCS simultaneously with abirterone weakens the stimulating effect of ACTH, which leads to a decrease in the frequency and severity of these adverse reactions.

With the withdrawal of prednisone or prednisolone, caution and control of symptoms of adrenal cortex deficiency is necessary. If the use of abiraterone continues after cancellation of the SCS, then the symptoms of an excess of mineralocorticoids should be monitored. In patients receiving prednisone or prednisolone, with the development of stressful situations, an increased dose of GCS may be required before, during and after a stressful situation.

Instructions

Abiraterone (Abirateronum)