Abiraterone

Abiraterone is an antineoplastic agent belonging to the pharmacological class of Androgen Biosynthesis Inhibitors.

Abiraterone Acetate is the prodrug form of Abiraterone. The FDA approves Abiraterone to treat metastatic castration-resistant prostate cancer (mCRPC) and metastatic high-risk castration-sensitive prostate cancer (mCSPC).

When administered orally, Abiraterone is absorbed from GIT and is highly bound (>99%) to the human plasma proteins, albumin, and alpha-1 acid glycoprotein. The liver carries out metabolism through hydroxylation, resulting in subsequent inactivation. The majority is excreted through faeces.

The most common side effects of Abiraterone include vomiting, decreased potassium levels in the blood, oedema (swelling), decreased white blood cell count, fatigue and increased liver enzymes.

Abiraterone is available as an oral tablet.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Abiraterone is an antineoplastic agent belonging to the pharmacological class of Androgen Biosynthesis Inhibitors.

The enzyme 17α-hydroxylase/C17,20-lyase (CYP17) is essential for the biosynthesis of androgens. Testicular, adrenal, and prostatic tumours are the main places where it is expressed. Pregnenolone and progesterone are 17α-hydroxylated by CYP17 to their 17α-hydroxy derivative. The C 20,21-acetyl group is then cleaved to produce androstenedione and dehydroepiandrosterone (DHEA). The precursors of testosterone are androstenedione and DHEA. Prostate cancers have been linked to abnormal androgen levels and dysregulated androgen receptor signalling, which can lead to cancer development and progression. Reduced androgen levels are a response to treatment for androgen-sensitive prostatic carcinoma. Treatments involving androgen deprivation, such as GnRH agonists or orchiectomy, reduce testicular androgen production but do not affect adrenal or tumorine androgen production.

Inhibiting CYP17, Abiraterone prevents the synthesis of androgens. Increased mineralocorticoid production by the adrenal glands is another effect of CYP17 inhibition.

The peak plasma time for Abiraterone is 2 hours.

Abiraterone is available as an oral tablet.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

The physician recommends taking this medication orally once or twice daily, with or without meals.

Abiraterone is indicated for treating metastatic castration-resistant prostate cancer (CRPC) in combination with prednisone.

In combination with methylprednisolone, Abiraterone is indicated for the treatment of patients with metastatic CRPC. In another context, Abiraterone is also indicated in combination with prednisone for managing metastatic high-risk castration-sensitive prostate cancer (CSPC).

Orally: Swallow the tablets whole with water; avoid chewing, crushing, or splitting. Take the medication once daily in combination with prednisone. Administer on an empty stomach; refrain from eating 2 hours before and 1 hour after taking it. Consume once daily with methylprednisolone twice daily, with or without food. In case of a missed dose of Abiraterone or corticosteroid (i.e., methylprednisolone or prednisone), resume the standard dose the following day.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Abiraterone is available as an oral tablet.

Dose Adjustment in Adult Patients:

High-risk hormone-sensitive metastatic prostate cancer

Once daily, 1,000 mg combined with androgen deprivation therapy and prednisone or prednisolone.

Metastatic castration-resistant prostate cancer

As conventional tab: 1,000 mg once daily when combined with prednisone or prednisolone.

As micronized tab: In combination methylprednisolone: 500 mg OD daily.

Dosage Modifications

Patients taking potent CYP3A4 inducers: As conventional tab: Raise the dose to 1,000 mg bid.

As micronized tab: Raise the dose to 500 mg bid.

There are no specific dietary requirements when taking Abiraterone. However, it is advised to include veggies like kale, cauliflower, cabbage, broccoli, spinach, and cabbage since they are known to lower the risk and slow the growth of prostate cancer. Dairy products should be consumed in moderation as they may increase the risk of prostate cancer. It is also advised to limit the consumption of red meat to lower the risk of prostate cancer, especially when cooked at high temperatures.

The dietary restriction should be individualized as per patient requirements.

• Severe hepatic impairment.
• Concomitant use with radium Ra-223.
• Pregnancy and lactation.
• Women who may become pregnant.

• If a patient has a history of cardiovascular disease, proceed with caution when giving them Abiraterone, and make sure they are closely monitored for excess mineralocorticoids. Patients with heart failure classified as Class III or IV by the New York Heart Association (NYHA) or with a left ventricular ejection fraction (LVEF) of less than 50% may not safely use Abiraterone. Before starting treatment, address hypertension and eliminate hypokalemia. Check serum potassium levels, blood pressure, and fluid retention symptoms monthly or more frequently.
• Closely observe for any indications or symptoms of adrenocortical insufficiency. Modify the dosage of corticosteroids as necessary before, during, and after stressful situations.
• Elevated liver enzymes, or hepatotoxicity, may require stopping, altering, or stopping the use of Abiraterone. Regularly check liver function and adjust the dosage of Abiraterone following prescribed guidelines.
• It is necessary to take Abiraterone on an empty stomach to maximize therapeutic efficacy. When Abiraterone acetate is taken with meals, exposure (the area under the curve) can increase up to ten times.

The adverse reactions related to Abiraterone can be categorized as:

• Common Adverse Effects: Dizziness, heartburn, headache, swelling (oedema), vomiting, decreased potassium levels, and white blood cell count.
• Less Common Adverse Effects: Urinary tract infections, increased liver enzymes, anaemia, high blood pressure, cough, and hypercholesterolemia.
• Rare Adverse Effects: Hepatotoxicity, hypertension, hypokalemia, and cardiac disorders.

Reports on Postmarketing

Disorders of the thoracic, mediastinal, and respiratory systems: Noninfectious pneumonitis

Disorders of the musculoskeletal system and connective tissue: myopathy, rhabdomyolysis included

Hepatobiliary disorders: Acute hepatic failure and death due to fulminant hepatitis

Disorders of the immune system: hypersensitivity, anaphylactic reactions (severe allergic reactions characterized by breathing difficulties, swelling of the face, lips, tongue, or throat, or itchy rash)

The clinically relevant drug interactions of Abiraterone are briefly summarized here.

• Potent CYP3A4 inducers, such as rifampicin, phenytoin, carbamazepine, rifapentine, rifabutin, and phenobarbital, cause a decrease in serum concentration. Drugs metabolized by CYP2D6 (e.g., dextromethorphan, thioridazine, codeine, oxycodone, tramadol, metoprolol, desipramine, venlafaxine, haloperidol, propafenone, risperidone, flecainide) may have a higher serum concentration. Class IA antiarrhythmics (quinidine, disopyramide), class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, and antipsychotics all increase the risk of QT prolongation. Reduced therapeutic benefit when using spironolactone.

Potentially lethal: Radium Ra 223 increases the risk of mortality and fractures.

• Food Interaction: High-fat meals may increase abiraterone exposure to the system. Reduced blood concentration when using St. John's wort.

• Pregnancy

Pregnancy Category X (FDA): When pregnant, avoid using. The risks outweigh the potential benefits. There are safer alternatives available.

Abiraterone is not recommended for use in pregnant women due to potential fetal harm and pregnancy loss, as well as findings from animal studies and mechanisms of action.

Not recommended for use in women

Regarding use in pregnant women, there is no human data available.

According to animal reproduction studies, oral abiraterone acetate administration during organogenesis to pregnant rats resulted in detrimental developmental effects at maternal exposures ~≥0.03 times the human exposure (AUC) at the recommended dose.

Contraception

Men who have female partners who may become pregnant should be advised to use effective contraception both during and for three weeks following the last abiraterone dose.

Infertility

may reduce fertility and reproductive function in males who are capable of reproducing, according to research on animals.

• Nursing Mothers

Not recommended for females

There is no information on abiraterone acetate's presence in human milk, its effects on nursing children, or how much milk they produce.

• Pediatric Use

The safety and effectiveness of Abiraterone in pediatric patients have not been established.

Dose Adjustment in Kidney Impairment Patients:

Mild-to-severe: No dosage adjustment is necessary

Dose Adjustment in Hepatic Impairment Patients:

Mild hepatic impairment: No dosage adjustment is necessary.

Moderate hepatic impairment (Child-Pugh Class B): Reduce the recommended dose of ZYTIGA to 250 mg once daily.

If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue Abiraterone treatment.

Severe hepatic impairment: Not studied; Not recommended.

Overdosing on Abiraterone during clinical trials has never been reported.

Management

There is no specific antidote for Abiraterone. In the event of an overdose, cease taking tablets of abiraterone acetate, monitor for arrhythmias and cardiac failure, and evaluate liver function, among other general supportive measures.

Pharmacodynamic

Cardiac Electrophysiology

In a multicenter, open-label, single-arm trial, 33 patients with metastatic colorectal cancer (CRPC) were given oral prednisone 5 mg twice a day along with 1,000 mg of abiraterone acetate tablets at least one hour before or two hours after a meal. On Day 2, no significant changes in the QTc interval (i.e., >20 ms) from baseline were observed in the assessments until Cycle 2. However, because of the limitations of the study design, small increases in the QTc interval (i.e., <10 ms) caused by abiraterone acetate cannot be ruled out.

Pharmacokinetics

• Absorption: Abiraterone acetate reaches peak plasma concentrations within approximately two hours when administered orally to metastatic castration-resistant prostate cancer (mCRPC) patients. Absorption is increased when taken with food.
• Distribution: Abiraterone exhibits extensive binding (>99%) to human plasma proteins, primarily albumin and alpha-1 acid glycoprotein, with a large volume of distribution (19,669 ± 13,358 L).
• Metabolism: Abiraterone is hydroxylated into its active form during metabolism, mainly in the liver. Abiraterone sulfate and N-oxide abiraterone sulfate are two examples of inactive metabolites produced due to additional metabolism by enzymes like CYP3A4 and SULT2A1.
• Excretion: Approximately 88% of Abiraterone and its metabolites are eliminated through faeces, and the remaining 5% are eliminated through urine. 14.4 to 16.5 hours is the range of the elimination half-lives.

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• https://www.ncbi.nlm.nih.gov/books/NBK548136/
• US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Zytiga® (abiraterone acetate)
• https://www.ncbi.nlm.nih.gov/books/NBK499548/
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