Enzalutamide

Introduction Overview

Generic Name

enzalutamide

Brand Name

Xtandi

Dosage Form

oral capsule (40 mg), oral tablet (40 mg; 80 mg)

Drug Class

Antiandrogens; Hormones / antineoplastics

Pharmacokinetics

Absorption:
Enzalutamide is well absorbed following oral administration, with peak plasma concentrations typically reached within 1 to 2 hours. The bioavailability is high, and food does not significantly affect its absorption, allowing flexible dosing with or without food. The drug's pharmacokinetics show dose-proportional increases across the therapeutic dosing range, supporting consistent systemic exposure. Clinical trials demonstrate steady-state concentrations are usually achieved within a few weeks of once-daily dosing.

Distribution:
Enzalutamide exhibits extensive tissue distribution, largely due to its lipophilicity. It is highly bound to plasma proteins (~97-98%), predominantly to albumin and alpha-1-acid glycoprotein, which influences its free active fraction. The volume of distribution is large, indicating widespread penetration into tissues including the prostate, which is the target organ in prostate cancer therapy. Studies suggest that it effectively crosses membranes to reach androgen receptor-expressing cells.

Metabolism:
Enzalutamide undergoes extensive hepatic metabolism primarily via cytochrome P450 enzymes, principally CYP2C8 and CYP3A4 isoforms. It is metabolized into active and inactive metabolites; notably, the major active metabolite has similar antiandrogenic activity as the parent compound. The metabolic pathway involves oxidative reactions and subsequent conjugation before elimination. Drug interactions influencing CYP2C8 or CYP3A4 can alter enzalutamide plasma levels, necessitating careful assessment of concomitant medications.

Elimination:
The elimination half-life of enzalutamide is approximately 5.8 days, supporting once-daily dosing. It is primarily eliminated via hepatic metabolism, with less than 1% excreted unchanged in urine. Excretion occurs through both feces and urine, predominantly as metabolites. The prolonged half-life and steady-state pharmacokinetics require monitoring in patients with liver impairment, although significant dose adjustments are generally not required in mild to moderate hepatic dysfunction. Renal impairment has minimal impact on drug clearance.

Dosage Forms

Available Dosage Forms:
- Oral capsule: 40 mg
- Oral tablet: 40 mg, 80 mg

Dosages for Adults and Adolescents:
The standard adult dosing regimen for enzalutamide in treating prostate cancer is 160 mg once daily, typically administered as four 40 mg capsules or tablets orally, with or without food. Patients must swallow the capsules or tablets whole without chewing, breaking, or crushing. This dosage is established for metastatic and non-metastatic castration-resistant prostate cancer.

Specific Patient Populations:
Elderly patients commonly use enzalutamide without dosage adjustment, with clinical trials including patients older than 65 years demonstrating similar efficacy and safety. There is scant data for pediatric use, and enzalutamide is not indicated for children or women. Patients with hepatic or mild to moderate renal impairment generally do not require dose modification; however, severe hepatic impairment data is limited. It is critical that patients concurrently undergo gonadotropin-releasing hormone (GnRH) analog therapy or have undergone bilateral orchiectomy for optimal efficacy.

Clinical Guidelines:
Dose adjustments during therapy are uncommon but clinical monitoring for adverse effects, especially neurological symptoms, is essential. Missed doses should be taken as soon as possible unless close to the next scheduled dose. Overdose management is primarily supportive, addressing potential seizure risk.

Mechanism Of Action

Enzalutamide acts primarily as a potent and selective inhibitor of the androgen receptor (AR), a nuclear receptor that mediates the effects of androgens such as testosterone and dihydrotestosterone (DHT). By competitively binding to specific ligand-binding domains on the AR, enzalutamide prevents androgens from activating the receptor, thus blocking the transcription of androgen-responsive genes that promote prostate cancer cell proliferation and survival.

Beyond simple competitive antagonism, enzalutamide exerts multiple inhibitory effects on the AR signaling pathway. It impairs AR nuclear translocation, preventing the receptor from entering the nucleus where it exerts transcriptional control. It also disrupts the AR's ability to bind DNA and recruit coactivators, further inhibiting downstream gene expression. These mechanisms result in decreased tumor growth and increased apoptosis in prostate cancer cells, including those resistant to conventional hormonal therapies.

Biochemically, enzalutamide's high affinity for the AR surpasses that of first-generation antiandrogens such as bicalutamide, conferring activity even in castration-resistant settings where AR overexpression or mutations may occur. Additionally, enzalutamide’s lack of partial agonist activity avoids receptor activation seen with older agents, improving therapeutic efficacy.

Clinical implications of these mechanisms include significant inhibition of prostate-specific antigen (PSA) levels and tumor progression in patients with advanced prostate cancer. The drug has demonstrated survival benefits in multiple randomized controlled trials. Research indicates its ability to penetrate the blood-brain barrier may contribute to central nervous system side effects, such as seizures, reflecting its impactful AR inhibition beyond peripheral tissues.

Pharmacological Actions

Potent and selective androgen receptor antagonist inhibiting androgen-mediated signaling.
Inhibits nuclear translocation of androgen receptor, blocking receptor-mediated gene transcription.
Prevents androgen receptor binding to DNA and recruitment of coactivators, suppressing gene expression.
Reduces proliferation and induces apoptosis of prostate cancer cells.
Active against castration-resistant prostate cancer by overcoming resistance mechanisms.
High binding affinity with no agonist activity, ensuring effective receptor blockade.
Modulates tumor microenvironment through androgen pathway inhibition.
May cross the blood-brain barrier, contributing to central nervous system pharmacodynamics.
Interferes with prostate-specific antigen (PSA) production reflecting tumor response.
Synergistic effects when combined with GnRH analogs or orchiectomy in testosterone suppression.

Therapeutic Or Clinical Uses

Treatment of metastatic castration-resistant prostate cancer (mCRPC).
Management of non-metastatic castration-resistant prostate cancer (nmCRPC) at high risk of metastasis.
Treatment of metastatic castration-sensitive prostate cancer (mCSPC).
Used in patients who have undergone surgical or chemical castration.
Adjunct therapy alongside gonadotropin-releasing hormone (GnRH) analogs or after bilateral orchiectomy.
Alternative treatment when prostate cancer progresses despite hormone therapy.
Off-label use in clinical trials for prostate cancer resistant to other antiandrogens.
Reduces prostate-specific antigen (PSA) levels to monitor treatment efficacy.
Potential use in combination regimens to enhance androgen pathway blockade.
Part of therapeutic protocols aiming to delay progression and improve survival in advanced prostate cancer.

Side Or Adverse Effects

Fatigue and feeling of weakness are commonly reported.
Hypertension, including severe elevations requiring intervention.
Central nervous system effects such as dizziness, headache, and seizure risk.
Gastrointestinal disturbances like constipation and diarrhea.
Loss of appetite leading to weight loss or nutritional concerns.
Musculoskeletal pain including back pain and joint discomfort.
Flushing and hot flashes due to hormonal alterations.
Increased risk of falls and bone fractures owing to dizziness or musculoskeletal effects.
Rare allergic reactions presenting as rash, hives, or angioedema.
Confusion, cognitive impairment, or other neurological symptoms.
Potential hematologic abnormalities observed during therapy.
Symptoms of infection including fever, cough, and shortness of breath.
Cardiac symptoms such as chest pain or exertional dyspnea in rare cases.
Urinary abnormalities including red or pink discoloration.
Elevated liver enzymes have been reported but are uncommon.

Precautions

Contraindicated in patients with known hypersensitivity to enzalutamide or excipients.
Use cautiously in patients with history of seizures, head trauma, or cerebral ischemia.
Monitor blood pressure regularly due to risk of hypertension.
Advise patients to avoid activities requiring alertness until effects on CNS are known.
Use effective contraception during treatment and for at least 3 months after discontinuation due to teratogenicity.
Avoid use in women, especially during pregnancy and breastfeeding.
Patients with cardiovascular disease should be carefully evaluated before initiation.
Monitor for signs of infection or pulmonary complications.
Evaluate liver function periodically during prolonged therapy.
Use caution when co-administered with drugs lowering seizure threshold.
Avoid abrupt discontinuation without medical supervision.
Instruct patients to swallow capsules or tablets whole to maintain therapeutic efficacy.
Educate about potential drug-drug interactions with CYP enzyme modulators.
Close monitoring in patients with diabetes or metabolic syndrome due to risk of exacerbation.
Assess neurologic status frequently in patients with prior CNS disorders.

Warnings

Can cause fetal harm or birth defects; strict pregnancy prevention required for patients and partners.
Risk of seizures increased, especially in patients with predisposing factors or concomitant medications.
May cause dizziness, somnolence, and impairment in driving or hazardous activities.
Potential for serious hypertension necessitating aggressive management.
Discontinue and seek medical attention if signs of hypersensitivity or severe CNS toxicity occur.
Use not recommended in pediatric populations or women.
Potential interactions with CYP2C8 and CYP3A4 inducers or inhibitors affecting drug levels.
Careful monitoring warranted in patients with prior cerebrovascular disease.
Significant risk of fall-related injuries, especially in elderly patients.
Possibility of immune suppression leading to increased infection risk.
Overdose may result in seizures requiring emergent care.
Prolonged QT interval and arrhythmia risk have not been extensively studied; use with caution.
Dosage modifications may be necessary in severe hepatic impairment.
Closely monitor blood pressure and neurological status during therapy.
Concomitant use with other antiandrogens or hormone therapies requires expert supervision.

Contraindication

Hypersensitivity to enzalutamide or any component of the formulation.
Use in women during pregnancy or breastfeeding.
Patients with a history of seizure disorders or conditions predisposing to seizures unless benefits outweigh risks.
Known severe hepatic impairment where safety and efficacy have not been established.
Concurrent use with medications known to significantly lower seizure threshold without careful monitoring.
Active severe cardiovascular disease that may be exacerbated by hypertension.
Pediatric patients due to lack of safety and efficacy data.
Patients unwilling to comply with effective contraception measures.
Known hypersensitivity reactions to other antiandrogen agents.
Use in patients with brain metastases associated with higher seizure risk.
Conditions with active central nervous system pathology where drug penetration could exacerbate symptoms.
Severe uncontrolled hypertension or poorly managed cardiac arrhythmias.
Severe uncontrolled infection or pulmonary disease without adequate control.
Use in combination with cytochrome P450 modulators that drastically alter enzalutamide levels without monitoring.
Non-approval for use in non-prostate cancer indications.

Drug Interactions

Enzalutamide is a strong inducer of CYP3A4 and CYP2C9, potentially reducing efficacy of concomitant drugs.
Co-administration with CYP2C8 inhibitors (e.g., gemfibrozil) may increase enzalutamide plasma concentrations.
Drugs that lower seizure threshold (e.g., bupropion, tramadol) may increase risk of seizures when used with enzalutamide.
Concurrent use with anticoagulants may require dose adjustments due to CYP enzyme induction.
Interaction with certain hormonal therapies may alter efficacy or toxicity profiles.
Use with immunosuppressants or corticosteroids requires caution due to increased infection risk.
Potential reduction in effectiveness of antidiabetics, antidepressants, and antipsychotics metabolized by CYP enzymes.
Herbal supplements (e.g., St. John's Wort) may decrease enzalutamide levels via CYP induction.
Avoid or monitor closely when used with strong CYP3A4 inhibitors or inducers.
May decrease plasma concentrations of drugs such as midazolam, simvastatin, and warfarin.
Interacts with anti-inflammatory agents that may also increase seizure risk.
Use caution with calcium channel blockers and other cardiovascular agents metabolized by CYP enzymes.
Vitamin K antagonists may require monitoring due to altered coagulation status.
Concomitant use with other antiandrogens or androgen deprivation therapies should be medically supervised.
Close monitoring advised for polypharmacy patients to detect unanticipated interactions.

Preparations Of The Drug

Oral capsules available in 40 mg strength designed for whole swallowing without chewing or opening.
Oral tablets provided in 40 mg and 80 mg dosing options offering flexibility in dose administration.
Pharmaceutical-grade capsules and tablets formulated for consistent bioavailability and stability.
Blister packaging and bottle presentations designed to protect from moisture and heat.
Dispensed with comprehensive patient information leaflets detailing proper administration.
Parenteral or alternative formulations are not currently approved or available.
Standard preparation requires no mixing or compounding prior to administration.
Recommended storage at controlled room temperature, avoiding excessive humidity or heat.
Manufactured under Good Manufacturing Practices with validated quality control.
Units are color-coded and imprinted for identification and to minimize medication errors.
Available as prescription-only medication requiring physician oversight.
Supply includes medication guides emphasizing seizure risks and birth defect warnings.
Supports once-daily dosing convenience to enhance patient adherence.
Compatibility with common pharmaceuticals confirmed; no known excipients causing significant allergies.
Preparation guidelines stress avoiding crushing or breaking to maintain integrity and controlled release properties.