DESCRIPTION
Mechanism of Action
• Prodrug of abiraterone
• Selective inhibition of 17a-hydroxylase/C17, 20-lyase (CYP17). This
enzyme is expressed in testicular, adrenal, and prostatic tumor tissues
and is required for androgen biosynthesis.
• Inhibition of CYP17 leads to inhibition of the conversion of pregnenolone
and progesterone to their 17a-hydroxy derivatives.
• Inhibition of CYP17 leads to inhibition of subsequent formation of
dehydroepiandrosterone (DHEA) and androstenedione.
• Associated with a rebound increase in mineralocorticoid production
by the adrenals.
Mechanism of Resistance
• Upregulation of CYP17.
• Induction of androgen receptor (AR) and AR splice variants that
result in ligand-independent AR transactivation.
• Expression of truncated androgen receptors.
Absorption
Following oral administration, maximum drug levels are reached within
1.5–4 hours. Oral absorption is increased with food, and in particular, food
with high fat content.
Distribution
Highly protein bound (.99%) to albumin and α-1 acid glycoprotein.
Metabolism
Following oral administration, abiraterone acetate is rapidly hydrolyzed to
abiraterone, the active metabolite. The two main circulating metabolites of
abiraterone are abiraterone sulphate and N-oxide abiraterone sulphate, both
of which are inactive. Nearly 90% of an administered dose is recovered in
feces, while only 5% is eliminated in urine. The terminal half-life of abiraterone
ranges from 5 to 14 hours, with a median half-life of 12 hours.
Indications
FDA-approved for use in combination with prednisone for the treatment
of patients with metastatic, castration-resistant prostate cancer who have
received prior chemotherapy containing docetaxel.
Dosage Range
Recommended dose is 1000 mg PO once daily in combination with
prednisone 5 mg PO bid.
Drug Interactions
• Use with caution in the presence of CYP2D6 substrates.
• Use with caution in the presence of CYP3A4 inhibitors and inducers.
Special Considerations
1. No dosage adjustment is necessary for patients with baseline mild
hepatic impairment. In patients with moderate hepatic impairment
(Child-Pugh Class B), reduce dose to 250 mg once daily. If elevations
in ALT or AST .5 3 ULN or total bilirubin .3 3 ULN occur in
patients, discontinue treatment. Avoid use in patients with severe
hepatic impairment, as the drug has not been tested in this patient
population.
2. No dosage adjustment is necessary for patients with renal impairment.
3. Abiraterone acetate should be taken on an empty stomach with no
food being consumed for at least 2 hours before and for at least 1
hour after an oral dose. Tablets should be swallowed whole with water.
4. Closely monitor for adrenal insufficiency, especially if patients are
withdrawn from prednisone, undergo a reduction in prednisone
dose, or experience concurrent infection or stress.
5. Pregnancy category X. Breastfeeding should be avoided.
Toxicity 1
Fatigue.
Toxicity 2
Mild nausea and vomiting.
Toxicity 3
Mild elevations in SGOT/SGPT.
Toxicity 4
Hypertension.
Toxicity 5
Peripheral edema.
Toxicity 6
Hypokalemia.
Toxicity 7
Arthralgias, myalgias, and muscle spasms.
Toxicity 8
Hot flashes.
SPECIFICATION
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