Abiraterone

Uses

Abiraterone is a CYP17 inhibitor used for combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

Abiraterone is also used to associated treatment for these conditions: Metastatic Castration Resistant Prostate Cancer

How Abiraterone works

Abiraterone is an orally active inhibitor of the steroidal enzyme CYP17A1 (17 alpha-hydroxylase/C17,20 lyase). It inhibits CYP17A1 in a selective and irreversible manner via covalent binding mechanism. CYP17A1 is an enzyme that catalyzes the biosynthesis of androgen and is highly expressed in testicular, adrenal, and prostatic tumor tissue. More specifically, abiraterone inhibits the conversion of 17-hydroxyprognenolone to dehydroepiandrosterone (DHEA) by the enzyme CYP17A1 to decrease serum levels of testosterone and other androgens.

Dosage

Abiraterone dosage

The recommended dose of Abiraterone is 1,000 mg (four 250 mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily. Abiraterone must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of Abiraterone is taken and for at least one hour after the dose of Abiraterone is taken. The tablets should be swallowed whole with water. Do not crush or chew tablets.

Side Effects

Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess, Adrenocortical Insufficiency Hepatotoxicity

Toxicity

Toxicity is related to the blockade of 17α-hydroxylase activity. Blockade results in the accumulation of upstream mineralocorticoids like 11-deoxycorticosterone leading to secondary hyperaldosteronism. Signs of hydroaldosteronism include fluid retention and hypokalemia. Mineralocorticoid receptor antagonists may be used to treat signs and symptoms.

Precaution

Abiraterone may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with Abiraterone.

Food Interaction

• Exercise caution with St. John's Wort. This herb induces CYP3A4 and may increase the serum levels of abiraterone.
• Take on an empty stomach. Take at least 1 hour before or 2 hours after eating as food may increase exposure to abiraterone by 4-fold.

[Moderate] ADJUST DOSING INTERVAL: Food may significantly increase the oral bioavailability of abiraterone acetate.

Compared to administration in the fasted state, abiraterone peak plasma concentration (Cmax) and systemic exposure (AUC) were approximately 7- and 5-fold higher, respectively, when a single dose of abiraterone acetate was administered with a low-fat meal (7% fat; 300 calories) and approximately 17- and 10-fold higher, respectively, when it was administered with a high-fat meal (57% fat; 825 calories).

Given the normal variation in the content and composition of meals, taking abiraterone acetate with meals has the potential to result in increased and highly variable exposures.

The safety of these increased exposures during multiple dosing has not been assessed.

MANAGEMENT: Abiraterone acetate must be taken on an empty stomach.

No food should be consumed for at least two hours before and one hour after the abiraterone acetate dose.

Abiraterone Drug Interaction

Moderate: tamsulosin, metoprololUnknown: charcoal, naproxen, fexofenadine, aspirin, ubiquinone, rosuvastatin, sodium iodide, insulin glargine, leuprolide, leuprolide, omeprazole, bioflavonoids, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, denosumab

Abiraterone Disease Interaction

Major: hepatic impairmentModerate: CVD

Volume of Distribution

Vdss= 19,669 ± 13,358 L

Elimination Route

Abiraterone itself is poorly absorbed and is susceptible to hydrolysis by esterases. The salt form, abiraterone acetate, is a prodrug which has a much higher oral bioavailability and is also esterase resistant. Peak drug concentrations of abiraterone were reached in 1.5 - 4 hours. Abiraterone acetate was rapidly and completely deacetylated into abiraterone-the parent salt form was not detectable in early pharmacokinetic studies. Food and high fat meals increases absorption 4.4-fold.

Half Life

Terminal elimination half-life = 5-14 hours

Elimination Route

Excreted via feces (~88%) and urine (~5%)

Pregnancy & Breastfeeding use

There are no human data on the use of Abiraterone in pregnancy and it is not for use in women of childbearing potential. Maternal use of a CYP17 inhibitor is expected to produce changes in hormone levels that could affect development of the foetus.

Pregnancy: Abiraterone is not for use in women. Abiraterone acetate is contraindicated in women who are or may potentially by pregnant (see Pharmacology: Toxicology: Preclinical Safety Data under Actions and Contraindications).

Breast feeding: Abiraterone is not for use in women. It is not known if either abiraterone acetate or its metabolites are excreted in human milk

Contraindication

Hypersensitivity to the Abiraterone acetate or to any of the excipients of Abiraterone. Women who may potentially be pregnant.

Acute Overdose

There have been no reports of overdose during clinical studies. There is no specific antidote. In the event of an overdose, administration should be withheld and general supportive measures undertaken, including monitoring for arrhythmias, hypokalaemia and for signs and symptoms of fluid retention. Liver function also should be assessed.

Storage Condition

Store below 30°C.

Innovators Monograph

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