ABIRAT 500

Indications

• Metastatic castration-resistant prostate cancer
• Metastatic hormone-sensitive prostate cancer in combination with prednisone

Dosage

Adults: The typical adult dose is 1000 mg once daily, taken in combination with prednisone 5 mg once daily.

Mechanism of action

Abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17), essential for androgen biosynthesis. By blocking this enzyme, abiraterone decreases the production of androgens such as testosterone from both the testes and adrenal glands. This reduction in androgen levels is significant for managing androgen-sensitive prostatic carcinoma, as it disrupts the hormonal environment that facilitates cancer growth.

Pharmacodynamics

After administration, abiraterone acetate is rapidly converted to abiraterone, which then exerts its pharmacological effect. The drug effectively lowers serum levels of testosterone and other steroid hormones, contributing to a decrease in prostate-specific antigen (PSA) levels, a marker used to monitor prostate cancer progression.

Pharmacokinetics

Abiraterone is administered orally and has a variable absorption profile. It is primarily metabolized in the liver, with CYP2D6 and CYP3A4 being the main enzymes involved in its biotransformation. The drug exhibits a half-life that allows for once-daily dosing. It is important to note that the presence of food can enhance the bioavailability of abiraterone, and therefore it is recommended to take it on an empty stomach.

Contra-indications

• Hypersensitivity to abiraterone or any of its components
• Pregnancy

Adverse effects

• Hypertension
• Hypokalemia
• Fluid retention
• Liver dysfunction
• Fatigue
• Hot flushes
• Diarrhea
• Nausea
• Vomiting

Interactions

• Rifampicin: Severe (decreases exposure)
• Eliglustat: Moderate (increases exposure)
• Selective beta-blockers: Unknown (increases exposure)
• Metoprolol: Unknown (increases exposure)
• Mitotane: Unknown (decreases exposure)

Precautions

• Monitor blood pressure regularly due to risk of hypertension
• Monitor potassium levels due to the risk of hypokalemia
• Caution in patients with liver impairment
• Ensure adequate contraceptive measures in patients of childbearing potential

Pregnancy

Abiraterone is contraindicated in pregnancy due to potential harm to a developing fetus.

Breast-feeding

It is unknown if abiraterone is excreted in human milk. Caution is advised.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Abiraterone acetate tablets

Indications

• Metastatic castration-resistant prostate cancer
• Hormone-relapsed prostate cancer before chemotherapy

Dosage

Adults: The recommended adult dose is 1,000 mg orally once daily, taken in combination with prednisone 5 mg orally once daily.

Mechanism of action

Abiraterone acetate is a selective inhibitor of CYP17A1, an enzyme involved in the biosynthesis of androgens. By inhibiting this enzyme, abiraterone reduces the production of testosterone and other androgens in the testes, adrenal glands, and tumor tissue. This leads to decreased androgen levels, which is crucial for the growth of prostate cancer cells.

Pharmacodynamics

Abiraterone acetate decreases serum testosterone levels and other adrenal androgens, contributing to the inhibition of tumor growth in androgen-dependent prostate cancer. The reduction of circulating androgens can lead to decreased cancer cell proliferation and increased apoptosis in the prostate cancer cells. Clinical studies have shown that abiraterone improves overall survival in patients with mCRPC.

Pharmacokinetics

Abiraterone acetate is administered orally and is extensively metabolized in the liver. It has a half-life of approximately 12 hours, with peak plasma concentrations occurring about 2 hours after administration. The drug exhibits high protein binding (approximately 99%) and is primarily excreted via feces, with a minor portion excreted in urine. Dose adjustments may be necessary in patients with hepatic impairment, as the drug is metabolized by cytochrome P450 enzymes.

Contra-indications

• Severe hepatic impairment
• Cardiac failure
• Uncontrolled hypertension

Adverse effects

• Fatigue
• Hypertension
• Hypokalaemia
• Gynaecomastia
• Diarrhoea
• Dyspepsia
• Bone fracture
• Angina pectoris
• Arrhythmias
• Meningioma risk with cyproterone acetate use

Interactions

• Phosphodiesterase inhibitors
• Androgens
• Anticoagulants
• CYP2D6 substrates

Precautions

• Monitor blood pressure and serum potassium concentration before and during treatment
• Caution in moderate hepatic impairment
• Use with caution in severe renal impairment
• Monitor liver function regularly

Pregnancy

Abiraterone acetate is not indicated for use in women and may be harmful to the fetus.

Breast-feeding

Use is not recommended in breastfeeding mothers.

Storage

Store in a cool, dry place away from light, at a temperature not exceeding 30°C.

Formulations

• Abiraterone acetate 250 mg film-coated tablets

Mechanism of action

17α-hydroxylase/C17,20-lyase (CYP17) is a key enzyme in androgen biosynthesis. It is primarily expressed in testicular, adrenal, and prostatic tumours. CYP17 catalyzes the 17α-hydroxylation of pregnenolone and progesterone to their 17α-hydroxy derivative, followed by subsequent cleavage of the C 20,21-acetyl group to yield dehydroepiandrosterone (DHEA) and androstenedione. DHEA and androstenedione are precursors of testosterone. Aberrant androgen levels and unregulated androgen receptor signalling have been implicated in the development and progression of various prostate cancers. Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumour. Abiraterone inhibits CYP17 to block androgen production. Inhibition of CYP17 can also result in increased mineralocorticoid production by the adrenals.

Pharmacodynamics

_In vivo_, abiraterone acetate is rapidly hydrolyzed to abiraterone, which mediates its pharmacological actions. Abiraterone decreases serum testosterone and other androgens. A change in serum prostate-specific antigen (PSA) levels may be observed.