Abiraterone Acetate

Name: Abiraterone Acetate

Uses for Abiraterone Acetate

Prostate Cancer

In combination with prednisone for the treatment of metastatic castration-resistant prostate cancer previously treated with docetaxel-containing therapy.1 4 18

Interactions for Abiraterone Acetate

Abiraterone is a potent inhibitor of CYP1A2 and CYP2D6, a moderate inhibitor of CYP isoenzymes 2C9, 2C19, and 3A4/5, and a substrate of CYP3A4 in vitro.1

Neither abiraterone acetate nor abiraterone is a substrate of P-glycoprotein (P-gp) in vitro at clinically relevant concentrations; abiraterone acetate inhibits P-gp.1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible increased serum concentrations of abiraterone.1 18 Avoid concomitant use or use with caution.1 (See Specific Drugs and Foods under Interactions.)

Potent CYP3A4 inducers: Possible decreased serum concentrations of abiraterone.1 18 Avoid concomitant use or use with caution.1 (See Specific Drugs and Foods under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6: Possible increased serum concentrations of CYP2D6 substrate drug and possible toxicity.1 18 Avoid concomitant use of abiraterone and CYP2D6 substrates with a narrow therapeutic index.1 15 If concomitant use cannot be avoided, consider dosage reduction of the CYP2D6 substrate drug and use with caution.1 15 (See Specific Drugs and Foods under Interactions.)

Substrates of CYP1A2: Pharmacokinetic interaction not observed to date.1

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antifungals, azoles (e.g., itraconazole, ketoconazole, voriconazole)

Possible increased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Antimycobacterials, rifamycins (e.g., rifabutin, rifampin, rifapentine)

Possible decreased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Carbamazepine

Possible decreased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Dextromethorphan

Increased peak concentrations and AUC of dextromethorphan1 2

Grapefruit or grapefruit juice

Possible increased abiraterone concentrations1 17 18

Avoid concomitant use or use concomitantly with caution1 17

HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)

Possible increased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Macrolides (clarithromycin, telithromycin)

Possible increased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Nefazodone

Possible increased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Phenobarbital

Possible decreased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Phenytoin

Possible decreased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Theophylline

No change in systemic exposure of single-dose theophylline1

Thioridazine

Possible increased thioridazine concentrations1 15 18

Avoid concomitant use; if concomitant use cannot be avoided, consider thioridazine dosage reduction and use with caution1 15

Abiraterone Acetate Pharmacokinetics

Absorption

Bioavailability

Abiraterone acetate is a prodrug that is converted in vivo to abiraterone; peak plasma abiraterone concentrations are attained about 2 hours after abiraterone acetate dose.1 5 13

Food

Food increases systemic exposure.1 8 13 Oral administration of a single 1-g dose of abiraterone acetate with a low-fat or high-fat meal increases abiraterone AUC by approximately fivefold or tenfold, respectively, and increases peak plasma concentrations by approximately sevenfold or 17-fold, respectively.1

Special Populations

In patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, AUC is increased 1.1- or 3.6-fold, respectively, compared with individuals with normal hepatic function.1

Distribution

Plasma Protein Binding

>99% (mainly albumin and α1-acid glycoprotein).1

Elimination

Metabolism

Abiraterone acetate is hydrolyzed to abiraterone (active metabolite), most likely by esterases in non-CYP-dependent pathways.1 Further metabolized to 2 inactive sulfate conjugates, abiraterone sulfate (formed by SULT2A1, a sulfotransferase that catalyzes sulfate conjugation of dehydroepiandrosterone [DHEA] and other steroids) and N-oxide abiraterone sulfate (formed by CYP3A4 and SULT2A1).1 19

Elimination Route

Excreted in feces (88%), mainly as abiraterone acetate (55%) and abiraterone (22%), and in urine (5%).1

Half-life

Approximately 12 hours.1

Special Populations

Mean half-life in patients with mild or moderate hepatic impairment is approximately 18 hours or 19 hours, respectively.1

In patients with end-stage renal disease requiring hemodialysis, pharmacokinetic parameters were similar to those in individuals with normal renal function.1

Advice to Patients

  • Importance of taking prednisone as directed to minimize adverse effects of abiraterone.1 If a dose of abiraterone or prednisone is missed, take the next dose at the regularly scheduled time; importance of advising clinician if more than one daily dose of abiraterone is missed.1

  • For patients currently receiving gonadotropin-releasing hormone (GnRH) agonist therapy, importance of continuing this therapy during abiraterone therapy.1

  • Risk of increased abiraterone exposure and adverse effects if the drug is taken with food.1 Importance of swallowing abiraterone acetate tablets whole with water and consuming no food for at least 2 hours before or 1 hour after a dose.1

  • Risk of peripheral edema, hypokalemia, hypertension, and urinary tract infection.1

  • Risk of hepatotoxicity and importance of liver function test monitoring.1

  • Importance of advising patients that abiraterone may cause fetal harm and that it is not known whether the drug distributes into semen.1 Necessity of advising men to use a condom during sexual encounters with pregnant women and to use a condom in conjunction with another effective contraceptive method during sexual encounters with women of childbearing potential; these contraceptive measures are required during and for 1 week after discontinuance of abiraterone therapy.1 Importance of advising patients that women who are or may be pregnant should not handle abiraterone acetate tablets without protection (e.g., gloves).1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Pharmacology

Selectively and irreversibly inhibits CYP17 (17 alpha-hydroxylase/C17,20-lyase), an enzyme required for androgen biosynthesis which is expressed in testicular, adrenal, and prostatic tumor tissues. Inhibits the formation of the testosterone precursors dehydroepiandrosterone (DHEA) and androstenedione.

Distribution

Vdss: 19,669 ± 13,358 L

Metabolism

Abiraterone acetate is hydrolyzed to the active metabolite abiraterone; further metabolized to inactive metabolites abiraterone sulphate and N-oxide abiraterone sulphate via CYP3A4 and SULT2A1

Excretion

Feces (~88%); urine (~5%)

Time to Peak

2 hours (Acharya 2012)

Half-Life Elimination

14.4 to 16.5 hours (Acharya 2012)

Protein Binding

>99%; to albumin and alpha1-acid glycoprotein

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

(web3)