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Medical Pharmacology Chapter 33-34: Anticancer Drugs
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Hormonal Anticancer Drugs:
Androgen receptor "superantagonist"3
Overview: Enzalutamide (Xtandi)
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Mechanism of Action:
Enzalutamide (Xtandi)
is considered a "superantagonist" because of its pure androgen receptor
"signaling" inhibitor characteristics.5
Enzalutamide has not been shown to exhibit agonist characteristics.
Enzalutamide androgen receptor inhibition includes:5
Inhibition of androgen receptor nuclear translocation
Inhibition of DNA binding
Inhibition of coactivator mobilization
Enzalutamide
administration promotes:
Apoptosis
Decreased prostate tumor volume.
Enzalutamide (Xtandi) is a recently approved second-generation
antiandrogen agent.
Initially approved in 2018 for castration-resistant prostate cancer treatment, Enzalutamide (Xtandi) was subsequently approved by the FDA for castration-sensitive prostate cancer in 2019.
Enzalutamide joins apalutamide (Erleada) in the second-generation nonsteroidal antiandrogen category1.
Enzalutamide, and antagonist acting at the androgen receptor, is a diarylthiohydantoin agent that binds to the androgen receptor within affinity notably greater that that observed with bicalutamide or flutamide.3
In addition to acting at the receptor:3
Enzalutamide interferes with nuclear translocation of androgen receptor
Impairs DNA-binding to androgen response elements
Inhibits coactivator recruitment.3
Absorption, Distribution, Biotransformation, Excretion:13
Enzalutamide is administered by the oral route of administration and can be taken with or without food.
This drug is substantially bound to plasma proteins (about 98%), mainly to serum albumin.
Biotransformation: Its active metabolite, N-desmethyl enzalutamide is also substantially bound (95%) to plasma proteins.
Enzalutamide is metabolized by the cytochrome P450 isoform CYP2C8 to an active metabolite N-desmethyl enzalutamide as well as by the isoform CYP3A4.
Elimination is mainly by liver metabolism.
The enzalutamide half-life (t1/2) is about 6 days.
The mean N-desmethyl enzalutamide terminal t1/2 is about 8 days.
Clinical Uses:
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Adverse Effects:
Common adverse reactions (>10%) (partial list) include:
Cardiovascular effects such as:
Peripheral edema
Hypertension
CNS effects including:
Fatigue
Dzziness
Headache
Endocrine and metabolic abnormalities such as:
Hyperglycemia
Gastrointestinal effects such as
Constipation
Diarrhea
Nausea
Appetite reduction.
Hematological effects including
Reduced neutrophils and
Decreased white blood cell count.
Respiratory and neuromuscular/skeletal effects also occur.
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