Darolutamide, sold under the brand name Nubeqa, is an

antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking t ...

medication which is used in the treatment of non-metastatic castration-resistant

prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...

in men. It is specifically approved to treat non-

metastatic Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...

castration-resistant prostate cancer Prostate cancer is the uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through screening tests, typically blood tests that che ...

(nmCRPC) in conjunction with

surgical Surgery is a medical specialty that uses manual and instrumental techniques to diagnose or treat pathological conditions (e.g., trauma, disease, injury, malignancy), to alter bodily functions (e.g., malabsorption created by bariatric surgery ...

medical castration Chemical castration is castration via anaphrodisiac drugs, whether to reduce libido and sexual activity, to treat cancer, or otherwise. Unlike surgical castration, where the gonads are removed through an incision in the body, ...

. The medication is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

twice per day with food.

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of darolutamide added to castration may include

fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

asthenia Weakness is a symptom of many different medical conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, ...

pain Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...

in the

arm In human anatomy, the arm refers to the upper limb in common usage, although academically the term specifically means the upper arm between the glenohumeral joint (shoulder joint) and the elbow joint. The distal part of the upper limb between ...

s and

leg A leg is a weight-bearing and locomotive anatomical structure, usually having a columnar shape. During locomotion, legs function as "extensible struts". The combination of movements at all joints can be modeled as a single, linear element cap ...

s, and

rash A rash is a change of the skin that affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracke ...

. Darolutamide is a

nonsteroidal antiandrogen A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens lik ...

(NSAA), and acts as a selective

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...

(AR). It has been referred to as a second- or third-generation NSAA. Darolutamide was patented in 2011 and was approved for medical use in USA in July 2019, in the European Union in March 2020 in Australia in July 2020. and in Canada in 2020,

Medical uses

Darolutamide is approved for use concurrently with a

gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and rele ...

(GnRH)

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.bilateral orchiectomy in the treatment of non-

(nmCRPC) in men. It is used at a dosage of 600 mg

orally The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or oral ...

twice per day (1,200 mg/day total) with food. In individuals with severe

renal impairment Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

or moderate hepatic impairment, darolutamide is used at a dosage of 300 mg orally twice per day (600 mg/day total) with food. No dosage adjustment is needed for mild to moderate renal impairment or mild hepatic impairment, whereas appropriate dosage adjustment for end-stage kidney disease and severe hepatic impairment is unknown. Two 2020

meta-analyses Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

reported that

enzalutamide Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castrati ...

and

apalutamide Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication used for the treatment of prostate cancer. It is an androgen receptor inhibitor. It is taken oral administration, by mouth. Side ef ...

seemed to be more effective than darolutamide in improving metastasis-free survival (MFS), however 2021 matched adjusted indirect comparison showed no significant differences between drugs in terms of MFS. According to 2021 meta-analysis darolutamide was ranked first in terms of improving overall survival (OS). Also, darolutamide showed significantly lower rate of grade 3-5 adverse events (AE) compared to both enzalutamide and apalutamide.

Available forms

Darolutamide is provided in the form of 300 mg

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

film-coated tablets.

Contraindications

Darolutamide has no

contraindication In medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a rea ...

s in men. However, the medication may have teratogenic effects in male

fetus A fetus or foetus (; : fetuses, foetuses, rarely feti or foeti) is the unborn offspring of a viviparous animal that develops from an embryo. Following the embryonic development, embryonic stage, the fetal stage of development takes place. Pren ...

es due to its

ic effects and hence should not be used by women who are

pregnant Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

Side effects

The most common

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of darolutamide in clinical trials (≥2% incidence) in castrated men included

and

(16% vs. 11% for

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

in extremities (6% vs. 3% for placebo), and

(3% vs. 1% for placebo). Darolutamide was also associated with higher incidences of

ischemic heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of heart disease involving the reduction of blood flow to the cardiac muscle due to a build-up of atheromatous plaque in the ...

(4.0% vs. 3.4% for placebo) and

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

(2.1% vs. 0.9% for placebo). In terms of laboratory test abnormalities, darolutamide was associated with decreased neutrophil count (20% vs. 9% for placebo), increased

aspartate aminotransferase Aspartate transaminase (AST) or aspartate aminotransferase, also known as AspAT/ASAT/AAT or (serum) glutamic oxaloacetic transaminase (GOT, SGOT), is a pyridoxal phosphate (PLP)-dependent transaminase enzyme () that was first described by Arthur ...

(AST) (23% vs. 14% for placebo; Grade 3–4: 0.5% vs. 0.2% for placebo), and increased

bilirubin Bilirubin (BR) (adopted from German, originally bili—bile—plus ruber—red—from Latin) is a red-orange compound that occurs in the normcomponent of the straw-yellow color in urine. Another breakdown product, stercobilin, causes the brown ...

(16% vs. 7% for placebo). In the clinical studies, 88% of patients treated with darolutamide were age 65 years or older. No

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

s have been observed with darolutamide in clinical trials. Darolutamide is an expected teratogen and has a theoretical risk of

birth defect A birth defect is an abnormal condition that is present at birth, regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can range from mild to severe. Birth de ...

s in male infants if taken by women during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

. It may impair male fertility. When used as a monotherapy (i.e., without surgical or medical castration) in men, NSAAs are known to produce

feminizing Feminization most commonly refers to: * Feminization (sociology), a perceived societal shift of gender roles toward the characteristically "female" * Feminization (biology), the hormonally induced development of female sexual characteristics * Fem ...

breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...

changes including

breast tenderness Breast pain is the symptom of discomfort in either one or both breasts. Pain in both breasts is often described as ''breast tenderness'', is usually associated with the menstrual period and is not serious. Pain that involves only one part of a ...

and

gynecomastia Gynecomastia (also spelled gynaecomastia) is the non-cancerous enlargement of one or both breasts in men due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse (10 Novemb ...

Overdose

Darolutamide has been studied at a dosage of up to 1,800 mg/day in clinical trials. There were no dose-limiting toxicities seen at this dosage. Due to its saturable

absorption Absorption may refer to: Chemistry and biology *Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which su ...

and lack of acute toxicity, overdose of darolutamide is not expected to result in systemic toxicity in people with intact hepatic and renal function. There is no specific

antidote An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon antidoton)'', "(medicine) given as a remedy". An older term in English which is ...

for overdose of darolutamide. In the event of darolutamide overdose, if there is no toxicity, treatment can be continued as normal. If there is suspicion of toxicity, general supportive measures should be undertaken until clinical toxicity has decreased or resolved and then treatment may be continued.

Interactions

Combined

P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

and strong or moderate

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

inducer In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely: *By disabling repressors. The gene is expressed because an inducer binds to the repressor. The binding of the inducer to the r ...

s such as

rifampicin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires' disease. It is almost always used tog ...

may decrease blood levels of darolutamide, while combined P-glycoprotein and strong CYP3A4

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

s such as

itraconazole Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given ...

may increase blood levels of darolutamide. Darolutamide is an inhibitor of the breast cancer resistance protein (BCRP) transporter and can increase blood levels of

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

s for BCRP protein, such as

rosuvastatin Rosuvastatin, sold under the brand name Crestor among others, is a statin medication, used to prevent cardiovascular disease in those at high risk and treat dyslipidemia, abnormal lipids. It is recommended to be used with dietary changes, exer ...

, by approximately 5-fold.

Pharmacology

Pharmacodynamics

Darolutamide is a second- or third-generation

(NSAA). It acts as a selective

competitive Competition is a rivalry where two or more parties strive for a common goal which cannot be shared: where one's gain is the other's loss (an example of which is a zero-sum game). Competition can arise between entities such as organisms, indi ...

silent antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of recep ...

of the

androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...

(AR), the

biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...

androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

s like

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

and

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production o ...

(DHT). Its affinity (K_i) for the AR is 11 nM and its functional inhibition () of the AR is 26 nM. The major

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

of darolutamide, ketodarolutamide, has similar antiandrogenic activity relative to darolutamide (K_i = 8 nM; IC₅₀ = 38 nM). In addition to its actions as an AR antagonist, darolutamide has been found to act as a silent antagonist of the

progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resi ...

(PR), with approximately 1% of the potency of its AR antagonism. A dosage of darolutamide of 1,200 mg/day has been found to result in a mean decrease in

prostate specific antigen The prostate is an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemically, and physiological ...

(PSA) levels of more than 90% in men with prostate cancer. The addition of darolutamide to castration has been found to decrease PSA levels by more than 50% in about 50% of men at 200 mg/day, 69% of men at 400 mg/day, 83% of men at 1,200 mg/day, and 86% of men at 1,400 mg/day. In accordance with its antiandrogenic activity, darolutamide monotherapy (600mg b.i.d.) has been found to increase

levels in men with prostate cancer by 43.3% on average (range 5.7 to 144.0%), from median 413ng/dL (range 209–1183ng/dL) at baseline to median 595ng/dL (range 260–1500ng/dL), after 24weeks of treatment. For comparison, testosterone levels increased by 114.3% with

monotherapy and high-dose bicalutamide monotherapy increases testosterone levels by about 59 to 97% in men with prostate cancer. A

phase 2 Michael Lawrence Marrow (August 2, 1955 – December 12, 2019), known as PHASE 2 and Lonny Wood, was an American aerosol paint artist based in New York City. Mostly active in the 1970s, Phase 2 is generally credited with originating the "bubble ...

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

directly comparing testosterone increases with darolutamide monotherapy versus enzalutamide monotherapy is underway as of January 2024. Darolutamide shows some advantages in comparison to enzalutamide and

, two other second-generation NSAAs. It has been claimed to negligibly cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

, and hence is thought to have a reduced risk of

s and other central

s from off-target GABA_A receptor inhibition. However, darolutamide monotherapy has subsequently been found to increase testosterone levels, a centrally mediated antiandrogenic action. Darolutamide has been found to block the activity of all tested/well-known mutant ARs in prostate cancer, including the recently identified clinically-relevant F876L mutation that produces resistance to enzalutamide and apalutamide. The medication shows higher affinity and inhibitory potency at the AR relative to enzalutamide and apalutamide ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' (K_i = 11 nM relative to 86 nM for enzalutamide and 93 nM for apalutamide; = 26 nM relative to 219 nM for enzalutamide and 200 nM for apalutamide). Darolutamide inhibits the

organic anion transporting polypeptide Organic may refer to: * Organic, of or relating to an organism, a living entity * Organic, of or relating to an anatomical organ Chemistry * Organic matter, matter that has come from a once-living organism, is capable of decay or is the product o ...

(OATP) transporters

OATP1B1 Solute carrier organic anion transporter family member 1B1 is a protein that in humans is encoded by the ''SLCO1B1'' gene. Pharmacogenomic research indicates that genetic variations in this gene are associated with response to simvastatin. Clinic ...

and OATP1B3 ''in vitro''. It shows no

inhibition Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransm ...

or induction of

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s (

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) at clinically relevant concentrations. Similarly, darolutamide shows no inhibition of a variety of other transporters (

MRP2 MRP2 may refer to: * Multidrug resistance-associated protein 2 * Manufacturing resource planning Manufacturing resource planning (MRP II) is a method for the effective planning of all resources of a manufacturing company. Ideally, it addresses op ...

, BSEP,

OAT The oat (''Avena sativa''), sometimes called the common oat, is a species of cereal grain grown for its seed, which is known by the same name (usually in the plural). Oats appear to have been domesticated as a secondary crop, as their seeds ...

s, OCTs,

MATE Mate may refer to: Science * Mate, one of a pair of animals involved in: ** Mate choice, intersexual selection *** Mate choice in humans ** Mating * Multi-antimicrobial extrusion protein, or MATE, an efflux transporter family of proteins Pers ...

s, OATP2B1,

NTCP Sodium/bile acid cotransporter also known as the Na+- taurocholate cotransporting polypeptide (NTCP) or liver bile acid transporter (LBAT) is a protein that in humans is encoded by the ''SLC10A1'' (solute carrier family 10 member 1) gene. Stru ...

) at therapeutic concentrations.

Pharmacokinetics

Absorption

The

absolute bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of darolutamide with

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

of a single 300-mg dose without food is approximately 30%. The bioavailability of darolutamide is increased by about 2- to 2.5-fold when administered with food, with a similar increase in exposure occurring for ketodarolutamide. Exposure to darolutamide and ketodarolutamide increases in a nearly linear or dose-proportional manner across a dose range of 100 to 700 mg (or about 0.17- to 1.17-fold the recommended 600-mg dosage). No further increase in exposure to darolutamide was observed at a dosage of darolutamide of 900 mg twice per day (or 1.5 times the recommended 600-mg dosage), indicating a saturation of absorption at doses above 700 mg. Following a single 600-mg dose of darolutamide, peak levels of darolutamide occur after approximately 4 hours. Steady-state levels of darolutamide occur after 2 to 5 days of continuous administration with food, during which time an approximate 2-fold accumulation in darolutamide levels occurs. At steady state with 600 mg/day darolutamide, mean levels of darolutamide are 4.79 μg/mL and area-under-the-curve levels of darolutamide over time 0 to 12 hours (AUC_0–12) are 52.82 h•μg/mL. Total exposure to ketodarolutamide is approximately 1.7-fold that of darolutamide.

Distribution

The

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

of darolutamide with

intravenous administration Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

is 119 L. The

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

of darolutamide is 92%, with 8% circulating freely, and of ketodarolutamide is 99.8%, with 0.2% circulating unbound. As such, free levels of darolutamide in the circulation are about 40-fold higher than those of ketodarolutamide. Both darolutamide and ketodarolutamide are bound mainly to

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

. Darolutamide and ketodarolutamide has been claimed to negligibly cross the

both in mice and humans. However, a subsequent study of darolutamide monotherapy in men with prostate cancer found that it increased testosterone levels, a centrally mediated antiandrogenic action. Darolutamide is a known

and the breast cancer resistance protein (BCRP). P-Glycoprotein is known to play a major role in excluding drugs from the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

due to efflux back across the

Metabolism

Darolutamide is primarily

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

into ketodarolutamide via

dehydrogenation In chemistry, dehydrogenation is a chemical reaction that involves the removal of hydrogen, usually from an organic molecule. It is the reverse of hydrogenation. Dehydrogenation is important, both as a useful reaction and a serious problem. At ...

in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

. The medication is also conjugated via

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...

UGT1A9 UDP-glucuronosyltransferase 1-9 is an enzyme that in humans is encoded by the ''UGT1A9'' gene. Function This gene encodes a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophilic molecules, suc ...

and

UGT1A1 UDP-glucuronosyltransferase 1-1, also known as UGT-1A, is an enzyme that in humans is encoded by the ''UGT1A1'' gene. UGT-1A is a uridine diphosphate glucuronosyltransferase (UDP-glucuronosyltransferase, UDPGT or UGT), an enzyme of the glucuroni ...

. The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of darolutamide and ketodarolutamide has been reported to be approximately 20 hours. A clinical study found that the elimination half-lives of darolutamide and ketodarolutamide at steady-state were 15.8 hours and 10.0 hours, respectively, with these half-lives being independent of dosage across a dose range of darolutamide of 200 to 1,800 mg/day. The elimination half-life of darolutamide is far shorter than that of

(e.g., 1.6 hours vs. 18.3 hours in mice). The clearance of darolutamide following intravenous administration is 116 mL/min.

Excretion

After a single oral dose of darolutamide, more than 95% of the dose is

excreted Excretion is elimination of metabolic waste, which is an essential process in all organisms. In vertebrates, this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific ...

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

and

feces Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...

within one week following administration. A total of 63.4% darolutamide-related material is recovered in urine (about 7% as unchanged darolutamide) and a total of 32.4% darolutamide-related material (about 30% as unchanged darolutamide) is recovered in

Variability

No clinically significant differences in the

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...

of darolutamide have been observed in men with nmCRPC on the basis of age (48 to 95 years), race (white, Asian, black), mild-to-moderate

, or mild hepatic impairment. In non-nmCRPC individuals with severe renal impairment not on

dialysis Dialysis may refer to: * Dialysis (chemistry), a process of separating molecules in solution **Electrodialysis, used to transport salt ions from one solution to another through an ion-exchange membrane under the influence of an applied electric po ...

, exposure to darolutamide was increased by about 2.5-fold relative to healthy people. In non-nmCRPC individuals with moderate hepatic impairment, darolutamide exposure was increased by about 1.9-fold compared to healthy controls. The pharmacokinetics of darolutamide have not been assessed in end-stage

kidney disease Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an Inflammation, inflammatory kidney disease and has several types according to the location of the inflammation. Infla ...

or severe hepatic impairment.

Chemistry

Darolutamide is a

nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor mo ...

compound Compound may refer to: Architecture and built environments * Compound (enclosure), a cluster of buildings having a shared purpose, usually inside a fence or wall ** Compound (fortification), a version of the above fortified with defensive struc ...

and is structurally distinct from other marketed NSAAs, including enzalutamide and apalutamide.

History

Darolutamide was developed by Orion Corporation and

Bayer HealthCare Bayer AG (English: , commonly pronounced ; ) is a German multinational pharmaceutical and biotechnology company and is one of the largest pharmaceutical companies and biomedical companies in the world. Headquartered in Leverkusen, Bayer's a ...

. Orion Corporation applied for a

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling discl ...

on darolutamide in October 2010, and this patent was published in May 2011. Darolutamide entered phase I

s in April 2011, with the results of the first clinical study of darolutamide initially published in 2012. The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) approved darolutamide in July 2019, under the agency's

priority review Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...

designation. Approval was based on ARAMIS, a multicenter, double-blind, placebo-controlled clinical trial in 1,509 patients with non-metastatic castration resistant prostate cancer. Patients were randomized (2:1) to receive either 600 mg darolutamide orally twice daily (n=955) or matching placebo (n=554). All patients received a gonadotropin-releasing hormone (GnRH) analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm. The primary endpoint was metastasis free survival (MFS), defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. The median MFS was 40.4 months (95% CI: 34.3, not reached) for patients treated with darolutamide compared with 18.4 months (95% CI: 15.5, 22.3) for those receiving placebo (hazard ratio 0.41; 95% CI: 0.34, 0.50; p<0.0001). Darolutamide was associated with greater benefits than placebo for all secondary end points, including overall survival (hazard ratio 0.69; 95% CI: 0.53-0.88; P=0.003), time to pain progression (median 40.3 months vs. 25.4 months; hazard ratio 0.65; 95% CI: 0.53-0.79; P<0.001), time to cytotoxic chemotherapy (hazard ratio 0.43; 95% CI: 0.31-0.60), and time to a symptomatic skeletal event (hazard ratio 0.43; 95% CI: 0.22-0.84).

Society and culture

Generic names

Darolutamide is the generic name of the medication and its and . It is also known by its developmental code names ODM-201 and BAY-1841788.

Brand names

Darolutamide is marketed under the brand name Nubeqa.

Availability

Darolutamide is available in the United States, Canada and the European Union.

Research

Darolutamide monotherapy is being studied in comparison to

androgen deprivation therapy Androgen deprivation therapy (ADT), also called androgen ablation therapy or androgen suppression therapy, is an antihormone therapy whose main use is in treating prostate cancer. Prostate cancer cells usually require androgen, androgen hormones, ...

with

GnRH agonist A gonadotropin-releasing hormone agonist (GnRH agonist) is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treat ...

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. As of 2018, it is entering a phase II

for this indication. In 2020, completion of this study had been expected in 2021 or 2022. Darolutamide is being studied for the treatment of

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

in women. As of November 2019, it is in phase II

s for this indication.

References

External links

* {{Portal bar , Medicine Antiprogestogens Carboxamides Chloroarenes Hormonal antineoplastic drugs Nitriles Nonsteroidal antiandrogens Peripherally selective drugs Pyrazoles