Abiraterone (Zytiga) for metastatic prostatic cancer

Abiraterone acetate is a prodrug of abiraterone (Zytiga). It blocks the production of androgen synthesis in the testis, adrenal glands, and tumor cells of the prostate by inhibiting the enzyme cytochrome P450 c17 (CYP17). Abiraterone ( Zytiga) as monotherapy or in combination with glucocorticoids has significant antitumor activity in patients with castration-resistant metastatic prostatic carcinoma.

Abiraterone acetate treatment improves life-expectancy in patients with prostate cancer:

In a phase-3 trial, Abiraterone acetate was found to improve survival in patients with metastatic castration-resistant prostate cancer who had received chemotherapy. A survival benefit was also seen in patients who had not received prior chemotherapy with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer. It is important to note that patients with the genetic mutations "androgen-receptor splice variant 7 messenger RNA (AR-V7)" may be resistant to Abiraterone and enzalutamide (Xtandi). Furthermore, sequential treatment with enzalutamide (Xtandi), a novel second-generation non-steroidal anti-androgen, has shown significant benefit in patients who progress despite abiraterone treatment. Apart from abiraterone and enzalutamide, the three other non-hormonal agents that are associated with increased survival in patients with prostate cancer are:

Docetaxel
Cabazitaxel
Sipuleucel-T

How is abiraterone acetate effective after castration?

Although castration results in a reduction in the testosterone levels, androgen production is increased by the adrenals and the tumor cells. Furthermore, there is an androgen-receptors up-regulation and increased sensitivity of the cells to testosterone.

Why prednisolone is given with abiraterone acetate?

Abiraterone blocks the adrenal androgens by blocking the enzyme cytochrome P450 c17 (CYP17). This results in an increase in the adrenal mineralocorticoids via the negative feedback mechanism causing hypertension, hypokalemia, and hypernatremia. Adding prednisolone to abiraterone treatment blocks the production of excess mineralocorticoids by blocking the production of ACTH via the negative feedback mechanism. Thus, prednisolone alleviates some of the important side effects of abiraterone treatment.

Abiraterone dose in Adults:

Metastatic castration-resistant prostate cancer:

1,000 mg orally once a day with prednisone 5 mg orally twice daily.

Metastatic castration-sensitive prostate cancer:

1,000 mg orally once a day with prednisone 5 mg orally once daily.

Patients receiving ZYTIGA (Abiraterone) should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

Zytiga dose in kidney disease:

Adjustments in the dose is not necessary.

Abiraterone dose adjustment in liver disease:

Liver disease prior to treatment initiation:

Mild (Child-Pugh class A):
- No dosage adjustment necessary.
Moderate (Child-Pugh class B):
- 250 mg once daily.
- Permanently discontinue treatment if ALT and/or AST is greater than 5 times the upper limit of normal (ULN) or total bilirubin is greater than 3 times the ULN.
Severe (Child-Pugh class C):
- Avoid use in advanced liver disease (child class C)

Hepatotoxicity during treatment:

U.S. labeling:

ALT and/or AST greater than 5 times the ULN or total bilirubin greater than 3 times ULN:
- Withhold the drug until the liver function tests return to baseline or ALT and AST are less than 2.5 times the ULN and total bilirubin is less than 1.5 times ULN
- Reinitiate treatment at a lower dose of 750 mg once a day.
Recurrent hepatotoxicity on 750 mg/day:
- Withhold treatment until liver function tests return to baseline or ALT and AST are less than 2.5 times ULN and total bilirubin less than 1.5 times ULN
- Reinitiate treatment at a lower dose of 500 mg once a day.
Recurrent hepatotoxicity on 500 mg/day:
- Discontinue treatment

Canadian labeling:

ALT and/or AST are greater than 5 times ULN or total bilirubin is greater than 3 times ULN:
- Withhold treatment until liver function tests return to baseline, then reinitiate at 500 mg once daily
Recurrent hepatotoxicity on 500 mg/day:
- Discontinue treatment
ALT greater than 20 times ULN (any time during treatment):
- Discontinue permanently

How to administer Abiraterone acetate tablets?

It should be taken orally on an empty stomach, at least one hour before and two hours after food. The tablets should be swallowed whole with water. Do not crush or chew the tablet.

Pregnancy Risk Category X

It is contraindicated in pregnant and lactating women.

Contraindications to Abiraterone (Zytiga)

A severe allergic reaction to any ingredient of the drug/preparation Women who may be pregnant or are currently pregnant.

Warnings and Precautions:

Adrenocortical Insufficiency
- It is administered concomitantly to prednisolone.
- This can cause adrenal crisis. If there is any infection or stress, the dose of steroids might need to be increased.
Hepatotoxicity:
- Patients should have liver function tests performed every two weeks for three months, and then monthly thereafter.
- Patients with liver disease, or elevated levels of liver enzymes (e.g. Zytiga) may be at risk for hepatotoxicity.
- Patients with abnormal liver function should stop Zytiga temporarily or reduce the dose.
- It has not been possible to evaluate retreatment for patients who have severe liver function abnormalities (ALT orAST > 20x the upper limit of normal, Bilirubin >10x the upper limit of normal).
Mineralocorticoid excess
- Hypertension, hypokalemia and fluid retention may be caused by increased mineralocorticoid activities due to CYP17 inhibition (including grade 3 or 4 events).
- These adverse events are less common when combined with prednisolone administration.
Cardiovascular disease
- Patients with heart disease should not take Zytiga (Abiraterone) seriously as it can cause hypertension, hypokalemia, and fluid overload.
- It should not be used in conjunction with May cause hypertension, hypokalemia and fluid retention. It should not be used in patients with a left-ventricular ejection fraction less than 50%.
Hepatic impairment
- Zytiga can be hepatotoxic, so patients with liver disease and those with abnormal liver function tests should avoid it.

Abiraterone side effects:

The most common adverse reactions (≥10%) are:

Cardiovascular:
- Hypertension
- edema
Central nervous system:
- Fatigue
- insomnia
Endocrine & metabolic:
- Hypertriglyceridemia
- hyperglycemia
- hypernatremia
- hypokalemia
- hypophosphatemia
- hot flash
Gastrointestinal:
- Constipation
- diarrhea
- dyspepsia
Genitourinary:
- Urinary tract infection
Hematologic & oncologic:
- Lymphocytopenia
- bruise
Hepatic:
- Increased serum alanine aminotransferase
- increased serum aspartate aminotransferase
- increased serum bilirubin
Neuromuscular & skeletal:
- Arthralgia
- joint swelling
- myalgia
Respiratory:
- Cough
- upper respiratory infection
- dyspnea
- nasopharyngitis

Less common side effects of Abiraterone:

Cardiovascular:
- Cardiac arrhythmia
- Chest discomfort
- Chest pain
- Cardiac failure
Central nervous system:
- Headache
- falling
Dermatologic:
- Skin rash
Genitourinary:
- Hematuria
- groin pain
- urinary frequency
- nocturia
Neuromuscular & skeletal:
- Bone fracture
Miscellaneous:
- Fever

Monitor:

ALT, AST and bilirubin (before starting the treatment, after 2 week, and every 3 months thereafter).
Patients with moderate hepatic dysfunction should monitor LFTs before starting therapy. LFTs should be monitored at baseline, then every two weeks for the first three months, then every two weeks for the next three and finally every month thereafter.
Hepatotoxicity can occur in patients who are treated. Patients must restart treatment once the LFTs have returned to baseline. Monitoring of liver functions should be increased (every 2 to 3 months, then every month thereafter).
Monitor serum potassium at baseline, and every month thereafter.
It is not necessary to monitor androgen levels (testosterone).
Monitor adrenal insufficiency, blood pressure, and fluid retention
You must ensure that you adhere to the rules.

Zytiga (Abiraterone) mechanism of Action:

ZYTIGA is a form of abiraterone acetate, which in vivo can be converted to abiraterone.
This is an androgen biosynthesis inhibitor that inhibits 17 ahydroxylase/C17.20-lyase (17 a-hydroxylase/CYP17).
This enzyme is found in the testicular, adrenal and prostatic tumor tissues.
It is necessary for androgen biosynthesis. DHEA, androstenedione, are androgens that are precursors to testosterone.
Abiraterone may also inhibit CYP17, which can lead to increased mineralocorticoid-producing adrenals.
Treatment that lowers androgen levels is a good option for prostatic cancer patients who are sensitive to Androgen.
Treatments with GnRH antagonists or orchiectomy can decrease androgen levels in the testes, but they do not affect the adrenals or the tumor's androgen production.

It is 99 percent protein-bound, and 88% is excreted through feces.