Darolutamide

BRAND NAMES

NUBEQA – Main marketed brand name of darolutamide.

Darolutamide – Generic name.

MECHANISM OF ACTION

Darolutamide is a non-steroidal androgen receptor inhibitor that acts by competitively blocking androgen receptors in prostate cancer cells. It prevents male hormones, such as testosterone and dihydrotestosterone (DHT), from binding to androgen receptors. This blocks androgen receptor activation, nuclear translocation and gene expression responsible for the growth and survival of prostate cancer cells. As a result, it inhibits cancer cell proliferation, reduces tumour growth and slows the progression of prostate cancer.

PHARMACOKINETICS

Absorption

Darolutamide is administered orally and absorbed through the gastrointestinal tract after taking the tablet. It has an absolute oral bioavailability of approximately 30% when taken on an empty stomach. The drug reaches its maximum plasma concentration (Cmax) approximately 4 hours after administration of a single dose. Food significantly increases its absorption and bioavailability by approximately 2 to 2.5 times compared with fasting conditions. Therefore, darolutamide is recommended to be taken with food to improve drug absorption and maintain adequate drug levels in the bloodstream. With regular twice-daily administration, steady-state concentration is generally achieved within 2–5 days.

Distribution

Darolutamide is widely distributed throughout the body after absorption into the bloodstream. It has a steady-state volume of distribution of approximately 119 litres, indicating distribution into body tissues. The drug shows high plasma protein binding of approximately 92%, mainly to albumin. Its active metabolite, keto-darolutamide, also exhibits high plasma protein binding. Darolutamide has limited penetration across the blood–brain barrier, resulting in low drug concentrations in the central nervous system. It reaches prostate cancer tissues, where it blocks androgen receptors and produces its therapeutic effect.

Metabolism

Darolutamide is primarily metabolized in the liver through oxidative metabolism by the cytochrome P450 enzyme CYP3A4. It is also metabolized through glucuronidation by UGT1A9 and UGT1A1 enzymes. During this process, darolutamide is converted into an active metabolite called keto-darolutamide, which has a higher plasma exposure than the parent drug. This metabolite is further converted through enzymatic processes before elimination from the body. Both darolutamide and its active metabolite contribute to the overall pharmacological activity.

Elimination

Darolutamide is eliminated from the body mainly through urine and feces after undergoing metabolism in the liver. Approximately 63.4% of the administered dose is excreted through urine, while about 32.4% is eliminated through feces. Only a small amount of the drug is excreted unchanged in urine, whereas a larger proportion is eliminated as metabolites. The effective elimination half-life of darolutamide and its active metabolite, keto-darolutamide, is approximately 20 hours. More than 95% of the administered dose is recovered within seven days after administration. Kidney and liver function play important roles in drug elimination, and patients with severe renal or hepatic impairment may require special monitoring.

PHARMACODYNAMICS

Darolutamide is a non-steroidal androgen receptor inhibitor that works by blocking the action of male hormones, particularly testosterone and dihydrotestosterone (DHT).This inhibits the movement of androgen receptors into the cell nucleus and reduces the expression of genes responsible for cancer cell growth and survival. It is used along with androgen deprivation therapy to reduce androgen stimulation and improve treatment outcomes.

ADMINISTRATION

It should be taken with food to improve absorption and maintain adequate drug levels in the bloodstream. The tablets should be swallowed whole with water and should not be crushed, chewed or broken. Darolutamide is generally given along with androgen deprivation therapy (ADT), such as a gonadotropin-releasing hormone (GnRH) analogue, or after surgical removal of the testes. Patients should take the medication regularly at the same time each day as prescribed by the physician.

DOSAGE AND STRENGTH

Darolutamide is available under the brand name NUBEQA as 300 mg film-coated tablets. The usual recommended adult dose is 600 mg (two 300 mg tablets) taken orally twice daily, giving a total daily dose of 1200 mg. It should be taken with food to improve absorption. The tablets should be swallowed whole with water without crushing or chewing. In patients with severe renal impairment or moderate hepatic impairment, the recommended dose is reduced to 300 mg twice daily. Dosage may also be adjusted depending on the patient's response to treatment and adverse effects. Treatment is generally continued until disease progression or unacceptable toxicity occurs.

DRUG INTERACTIONS

Darolutamide may interact with several medications and affect their concentration and therapeutic effectiveness. Strong or moderate CYP3A4 and P-glycoprotein (P-gp) inducers, such as rifampicin, carbamazepine and phenytoin, may decrease darolutamide levels and reduce its effectiveness. Darolutamide can also increase the blood levels of medicines transported by BCRP and OATP1B1/OATP1B3, such as rosuvastatin, increasing the risk of drug-related toxicity. Therefore, careful monitoring is required when darolutamide is used with other medications, and dose adjustments may be necessary.

FOOD INTERACTIONS

Taking the medicine with food increases its bioavailability by approximately 2–2.5 times compared with taking it on an empty stomach. Therefore, darolutamide should always be taken with food to improve absorption and maintain adequate drug levels in the bloodstream. Grapefruit and grapefruit juice should be avoided during treatment because they may affect drug metabolism and increase the risk of side effects. Patients should maintain a regular meal schedule and follow the prescribed administration instructions to achieve better therapeutic effectiveness.

CONTRAINDICATIONS

Darolutamide is contraindicated in patients with known hypersensitivity or allergic reactions to darolutamide or any of its ingredients. It should not be used by women who are pregnant or may become pregnant because it can cause harm to the developing fet us. It is not indicated for use in children. Caution is required in patients with severe kidney or liver impairment, cardiovascular disorders and a history of seizures. Patients should undergo proper medical evaluation before starting treatment to ensure safe and effective use.

SIDE EFFECTS

• Fatigue and weakness

• Increased liver enzymes (AST and ALT)

• Decreased white blood cell count (neutropenia)

• Increased bilirubin levels

• Skin rash

• Pain in extremities

• Constipation

• Decreased appetite

• Nausea

• Weight gain

• High blood pressure (hypertension)

• Anemia

Over Dose

Overdose of darolutamide may result from taking a higher dose than prescribed. Clinical studies have evaluated doses up to 900 mg twice daily without observing dose-limiting toxicity. However, the safety of excessive doses is not fully established, particularly in patients with kidney or liver impairment. There is no specific antidote available for darolutamide overdose. Management involves immediate medical evaluation, supportive treatment and monitoring of the patient's clinical condition.

TOXICITY

Darolutamide toxicity may occur due to excessive drug exposure or increased drug accumulation, particularly in patients with severe kidney or liver impairment. It may cause adverse effects such as fatigue, weakness, skin rash, increased liver enzymes, decreased white blood cell count, constipation and increased bilirubin levels. In some patients, serious complications such as ischemic heart disease and seizures may occur. Darolutamide has no known specific antidote for toxicity. Management involves medical evaluation, monitoring of liver and kidney function, supportive treatment and dose adjustment or temporary discontinuation under medical supervision.