Darolutamide
Darolutamide Uses, Dosage, Side Effects, Food Interaction and all others data.
Darolutamide is a nonsteroidal androgen receptor antagonist for the treatment of castrate-resistant, non-metastatic prostate cancer (nmCRPC). This condition occurs in the majority of patients with advanced prostate cancer who have been treated with androgen receptor antagonists. Though prior treatment for prostate cancer has been successful for these patients, the cancer eventually progresses to become resistant to existing therapies. This warrants further treatment.
The goal of treatment with darolutamide is to delay the progression of prostate cancer to metastatic disease, increasing quality of life and life expectancy for those with advanced prostate cancer. Darolutamide was developed by Bayer HealthCare Pharmaceuticals Inc. and approved by the FDA on July 30th, 2019.
Darolutamide, through its downstream effects on cancer cell growth, treats castrate-resistant prostate cancer. It inhibits cancer cell growth and markedly lowers prostate specific antigen (PSA) levels through potent androgen receptor antagonism.
| Trade Name | Darolutamide |
| Availability | Prescription only |
| Generic | Darolutamide |
| Darolutamide Other Names | Darolutamide |
| Related Drugs | estradiol, Premarin, Xtandi, Casodex, Zytiga, Lynparza |
| Weight | 300mg |
| Type | Oral tablet |
| Formula | C19H19ClN6O2 |
| Weight | Average: 398.85 Monoisotopic: 398.1258016 |
| Protein binding | The plasma protein binding for darolutamide is 92% and 99.8% for keto-darolutamide, the active metabolite. They are mainly bound to albumin. |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Darolutamide is an androgen receptor antagonist used for castration-resistant, non-metastatic prostate cancer.
This drug is indicated for the treatment of patients diagnosed with non-metastatic and castrate-resistant prostate cancer.
Darolutamide is also used to associated treatment for these conditions: Non-mestatatic castrate-resistant prostate cancer
How Darolutamide works
The actions of androgens on androgen receptors (AR) potentiate the growth and survival of prostate cancer cells. Darolutamide competitively inhibits androgens from binding to their receptors, inhibiting AR nuclear translocation, as well as AR-mediated transcription. The end result of these processes is a decrease in prostate cancer cell proliferation and tumor size. Its main metabolite, keto-darolutamide, shows similar pharmacological activity to the parent drug, darolutamide. Darolutamide has been found to bind more tightly to the AR receptor than apalutamide and enzalutamide, which are other androgen receptor antagonists.
Darolutamide can act as a progesterone receptor (PR) antagonist in the laboratory setting with approximately 1% activity when compared to its actions at the androgen receptor. The clinical relevance is not known at this time.
Toxicity
LD50 information for darolutamide is not readily available in the literature.
Overdose information
To this date, there is no known antidote in existence for an overdose with darolutamide. The highest dose clinically documented was a twice daily dose of 900 mg, totalling 1800 mg. Dose-limiting toxicities have not been observed with this drug. In patients with healthy kidney and liver function, a high dose of darolutamide will likely not lead to systemic toxicity. If a high dose (higher than recommended on labeling) is ingested in a patient with renal or hepatic impairment, and toxic symptoms occur, pause treatment with darolutamide and offer supportive treatment until symptoms resolve.
Food Interaction
- Avoid St. John's Wort. This herb induces CYP3A and P glycoprotein and may reduce the serum concentration of darolutamide.
- Take with food. This increases the bioavailability of darolutamide.
[Moderate] ADJUST DOSING INTERVAL: Food enhances the oral absorption of darolutamide.
According to the prescribing information, bioavailability of darolutamide increased by 2.0 to 2.5-fold when administered with food.
A similar increase in exposure was observed for the active metabolite keto-darolutamide.
MANAGEMENT: Darolutamide should be administered with food.
Darolutamide Drug Interaction
Moderate: doxorubicinUnknown: paclitaxel protein-bound, aspirin, aspirin, diphenhydramine, ticagrelor, bicalutamide, celecoxib, albuterol / ipratropium, ubiquinone, duloxetine, apixaban, fluticasone, adalimumab, insulin glargine, pregabalin, polyethylene glycol 3350, cyanocobalamin, ascorbic acid, cholecalciferol
Darolutamide Disease Interaction
Volume of Distribution
After intravenous administration, the apparent volume of distribution of darolutamide is about 119L.
Elimination Route
Darolutamide is absorbed in the gastrointestinal tract. In the fasted state, peak concentrations are reached within 3-5 hours, and within 3-8 hours in the fed state. Median Tmax is between 3-6 hours.The average darolutamide steady-state peak plasma concentration after a 600 mg twice daily dose is approximately 4.79 mg/L. The Cmax is attained approximately 4 hours after administration of a single 600 mg oral dose. The AUC 0-12h is approximately 52.82 h•μg/mL.
Effects of food
The absolute bioavailability of darolutamide is approximately 30% after fasting and taking a single 300 mg dose. Steady-state concentrations are attained between 2 and 5 days after repeated administration with food. The bioavailability of darolutamide increases by 2.0 to 2.5 times when it is given with food.
Half Life
The half-life of darolutamide and its active metabolite, keto-darolutamide is about 20 hours. A phase 1 study determined a terminal half life ranging between 10-15 hours.
Clearance
The clearance of darolutamide after an intravenous dose is 116 mL/min (39.7%).
Elimination Route
In a pharmacokinetic study, a radiolabeled dose of darolutamide in an oral solution showed that 63.4% of darolutamide-related material was excreted in the urine (7% of which was unchanged drug) and 32.4% in the feces (with 30% unchanged drug).
Innovators Monograph
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