Artesto Mechanism of Action

Pharmacotherapeutic group: endocrine therapy, other hormone antagonists and related agents. ATC code: L02BX03.
Pharmacology: Pharmacodynamics: Mechanism of action: Abiraterone acetate converted in vivo to abiraterone, an androgen biosynthesis inhibitor. Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in and is required for androgen biosynthesis in testicular, adrenal and prostatic tumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosterone precursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals (see Precautions).
Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with LHRH analogues or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumour. Treatment with abiraterone acetate tablets decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH analogues (or orchiectomy).
Pharmacodynamic effects: Abiraterone acetate tablets decrease serum testosterone and other androgens to levels lower than those achieved by the use of LHRH analogues alone or by orchiectomy. This results from the selective inhibition of the CYP17 enzyme required for androgen biosynthesis.
Pharmacokinetics: Abiraterone acetate is rapidly converted in vivo to abiraterone, an androgen biosynthesis inhibitor (see Pharmacodynamics as previously mentioned).
Absorption: Following oral administration of abiraterone acetate in the fasting state, the time to reach maximum plasma abiraterone concentration is approximately 2 hours.
Administration of abiraterone acetate with food, compared with administration in a fasted state, results in up to a 10-fold (AUC) and up to a 17-fold (C_max) increase in mean systemic exposure of abiraterone, depending on the fat content of the meal. Given the normal variation in the content and composition of meals, taking abiraterone acetate tablets with meals has the potential to result in highly variable exposures. Therefore, abiraterone acetate tablets must not be taken with food. It should be taken at least one hour before or at least two hours after eating.
The tablets should be swallowed whole with water (see Recommended Dosage under Dosage & Administration).
Distribution: The plasma protein binding of 14C-abiraterone in human plasma is 99.8%. The apparent volume of distribution is approximately 5,630 L, suggesting that abiraterone extensively distributes to peripheral tissues.
Biotransformation: Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolysed to abiraterone, which then undergoes metabolism including sulphation, hydroxylation and oxidation primarily in the liver. The majority of circulating radioactivity (approximately 92%) is found in the form of metabolites of abiraterone. Of 15 detectable metabolites, 2 main metabolites, abiraterone sulphate and N-oxide abiraterone sulphate, each represents approximately 43% of total radioactivity.
Elimination: The mean half-life of abiraterone in plasma is approximately 15 hours in healthy subjects. Following oral administration of 14C-abiraterone acetate 1,000 mg, approximately 88% of the radioactive dose is recovered in faeces and approximately 5% in urine. The major compounds present in faeces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).
Hepatic impairment: The use of abiraterone acetate should be cautiously assessed in patients with moderate hepatic impairment in whom the benefit clearly should outweigh the possible risk (see Recommended Dosage under Dosage & Administration and Precautions). Abiraterone acetate should not be used in patients with severe hepatic impairment (see Recommended Dosage under Dosage & Administration, Contraindications and Precautions).
For patients who develop hepatotoxicity during treatment, suspension of treatment and dose adjustment may be required (see Recommended Dosage under Dosage & Administration and Precautions).
Renal impairment: Administration in patients with renal impairment, including severe renal impairment, does not require dose reduction (see Recommended Dosage under Dosage & Administration). However, there is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is advised in these patients.