Apalutamide

MECHANISM OF ACTION

Apalutamide functions by inhibiting androgen receptors (ARs) in prostate cancer cells, blocking the effects of androgens such as testosterone, even in castration-resistant cases. It binds directly to the ligand-binding domain of the AR, preventing the receptor from entering the nucleus and attaching to DNA, thereby shutting down the AR-driven signaling pathways that support cancer cell growth and survival.

PHARMACOKINETICS

Absorption

Apalutamide is nearly completely absorbed, with an oral bioavailability close to 100%, and can be taken with or without food, although food may slightly delay the time to reach peak concentration. It attains peak plasma levels approximately 2 hours after dosing and undergoes extensive metabolism, mainly through the CYP3A4 and CYP2C8 enzymes, forming an active metabolite called N-desmethyl apalutamide. The drug has a long half-life of about 3 days. For patients unable to swallow tablets, apalutamide can be administered via feeding tubes by dispersing the tablet in water.

Distribution

The average apparent volume of distribution of apalutamide at steady state is approximately 276 liters.

Metabolism

Apalutamide is mainly metabolized in the liver by cytochrome P450 enzymes, predominantly CYP2C8 and CYP3A4, producing the active metabolite N-desmethylapalutamide (M3) and an inactive metabolite (M4). An important feature of its metabolism is strong autoinduction of CYP3A4, meaning it accelerates its own breakdown as well as that of other CYP3A4 substrates, which can significantly lower the levels of drugs like warfarin or apixaban, requiring dose adjustments or avoidance. The drug and its metabolites are eliminated through both urine and feces.

Excretion

Apalutamide is primarily eliminated through feces, accounting for approximately 65% of the administered dose, mostly as metabolites, while about 24% is excreted in urine, also mainly as metabolites. Only a very small fraction, less than 1%, is excreted as unchanged drug.

PHARMACODYNAMICS

Apalutamide is a non-steroidal anti-androgen that works by selectively binding to androgen receptors (ARs) in prostate cancer cells, blocking the action of androgens like testosterone and dihydrotestosterone. By preventing AR activation, it inhibits receptor translocation to the nucleus, DNA binding, and transcription of androgen-responsive genes that drive cancer cell growth and survival. Unlike traditional androgen deprivation therapies, apalutamide directly inhibits AR signaling even in castration-resistant prostate cancer, slowing disease progression and reducing the risk of metastasis.

DOSAGE AND ADMINISTRATION

Standard dose: 240 mg orally once daily (usually 4 × 60 mg tablets)

Administration: Can be taken with or without food

Special instructions:

• Swallow tablets whole, or for patients with swallowing difficulties, tablets can be dispersed in water and administered via a feeding tube.

• Take the medication at the same time every day to ensure steady and consistent drug levels in the body.

Adjustment: Dose modifications may be required for severe hepatic impairment or significant drug interactions, especially with strong CYP2C8 or CYP3A4 inhibitors/inducers.

DRUG INTERACTIONS

Apalutamide can interact with several drugs because it induces CYP3A4 and CYP2C8, which may reduce the effectiveness of medications metabolized by these enzymes, such as warfarin, apixaban, some statins, and oral contraceptives. Its levels can also be affected by strong CYP3A4 or CYP2C8 inhibitors or inducers, and caution is advised with drugs that prolong the QT interval or have liver toxicity. Dose adjustments or alternative therapies may be needed to manage these interactions.

FOOD INTERACTIONS

Apalutamide can be taken with or without food, as food does not significantly affect its overall absorption or bioavailability. However, a meal may slightly delay the time to reach peak plasma levels, but this does not impact its effectiveness. No specific dietary restrictions are required while taking the drug.

CONTRAINDICATIONS

Apalutamide is contraindicated in patients with a known hypersensitivity to apalutamide or any of its components. It should not be used in women who are pregnant or breastfeeding, as it may cause harm to the fetus or infant. Additionally, caution is required in patients with severe liver impairment, as safety and efficacy have not been established in this population.

SIDE EFFECTS

• Fatigue or extreme tiredness.

• Rash.

• Hypertension.

• Diarrhea.

• Nausea.

• Weight loss and decreased appetite.

• Arthralgia.

• Falls.

• Hot flashes.

• Fractures.

• Peripheral edema.

OVERDOSE

In case of an apalutamide overdose, no specific antidote is available. The medication should be discontinued immediately, and patients should receive supportive and symptomatic care until signs of toxicity lessen or resolve. Adverse effects observed in overdose are expected to resemble the common and serious side effects seen with routine therapeutic use of the drug.

TOXICITY

Apalutamide is generally well tolerated, but toxicity can occur, especially at higher doses or in sensitive patients. Common toxic effects include fatigue, rash, falls, hypertension, diarrhea, nausea, and hot flashes. Serious toxicities may involve severe skin reactions, fractures, cardiovascular events, and seizures. Liver function abnormalities and rare hypersensitivity reactions have also been reported.