Chemical formula: C₁₉H₁₉ClN₆O₂ Molecular mass: 398.85 g/mol PubChem compound: 67171867
Darolutamide is an androgen receptor (AR) inhibitor with a flexible polar-substituted pyrazole structure that binds with high affinity directly to the receptor ligand binding domain. Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR mediated transcription. A major metabolite, keto-darolutamide, exhibited similar in vitro activity to darolutamide. Darolutamide treatment decreases prostate tumour cell proliferation leading to potent antitumour activity.
No prolongation of the mean QTcF interval (i.e., greater than 10 ms) was observed after oral administration of 600 mg darolutamide twice daily compared to placebo.
Darolutamide consists of two diastereomers [(S,R)-darolutamide and (S,S)-darolutamide] which interconvert via the main circulating metabolite called keto-darolutamide. In vitro, all three substances show similar pharmacological activity. Darolutamide is poorly soluble in aqueous solvents over a large pH range and generally more soluble in organic solvents.
Following oral administration of 600 mg (2 tablets of 300 mg) twice daily, peak plasma concentrations of darolutamide at steady state were 4.79 mg/L (coefficient of variation: 30.9%) in nmCRPC patients in the ARAMIS study and 3.84 mg/L (coefficient of variation: 35.6%) in mHSPC patients in the ARASENS study. Median time to achieve peak plasma concentrations was 3 to 4 hours. The ratio of the two diastereomers, (S,R)-darolutamide to (S,S)-darolutamide, changed from a 1:1 ratio in the tablet to an approximately 1:9 ratio in plasma based on AUC0-12 data at steady-state. Following oral administration together with food, steady-state is reached after 2-5 days of repeated twice-daily dosing.
The absolute bioavailability compared to an intravenous injection is approximately 30% following oral administration of a darolutamide tablet containing 300 mg darolutamide under fasted conditions. Bioavailability of darolutamide was enhanced by 2.0- to 2.5-fold when administered with food. A similar increase of exposure was observed for the major metabolite keto-darolutamide.
The apparent volume of distribution of darolutamide after intravenous administration is 119 L indicating that darolutamide is widely distributed throughout the body to both intracellular and extracellular fluid spaces.
Darolutamide is moderately (92%) bound to human plasma proteins without any difference between the two diastereomers. The major metabolite of darolutamide, keto-darolutamide, is highly (99.8%) bound to plasma proteins.
Passage of darolutamide across the blood-brain barrier has not been studied clinically. However, brain exposures to darolutamide in terms of AUC0-24 are very low with 4.5% of plasma exposure after single dose in rats and 1.9-3.9% after repeated dose in mice. This indicates low passage of darolutamide across the intact blood-brain barrier in rats and mice and a low likelihood that darolutamide crosses the intact blood-brain barrier in humans to a clinically relevant extent.
The diastereomers (S,R)-darolutamide and (S,S)-darolutamide are able to interconvert via the metabolite keto-darolutamide with a preference for (S,S)-darolutamide.
Following single oral administration of 300 mg14 C-darolutamide given as an oral solution, keto-darolutamide is the only major metabolite with about 2-fold higher total exposure in plasma compared to darolutamide. Darolutamide and keto-darolutamide accounted together for 87.4% of the 14C-radioactivity in plasma indicating that all other metabolites are of minor importance. Darolutamide is metabolised primarily by oxidative metabolism mediated mainly by CYP3A4, as well as by direct glucuronidation mediated preferentially by UGT1A9 and UGT1A1. In addition, mainly the AKR1C isoforms were shown to catalyse the reduction of keto-darolutamide to the substance diastereomers.
The effective half-life of darolutamide and keto-darolutamide in plasma of patients is approximately 18 to 20 hours. Of the two diastereomers comprising darolutamide, (S,R)-darolutamide has a shorter effective half-life of 9 hours compared to (S,S)-darolutamide with an effective half-life of 22 hours. The clearance of darolutamide following intravenous administration was 116 mL/min (CV: 39.7%). A total of 63.4% of substance-related material is excreted in the urine (approximately 7% unchanged), 32.4% is excreted in the faeces. More than 95% of the dose was recovered within 7 days after administration.
In the dose range of 100 to 700 mg (after single dose and at steady state), the exposure to the two diastereomers and the major metabolite keto-darolutamide increases linearly in a nearly dose-related manner. Based on a saturated absorption, no further increase in exposure to darolutamide was observed at 900 mg twice daily.
No clinically relevant differences in the pharmacokinetics of darolutamide were observed (65-95 years).
In a clinical pharmacokinetic study, AUC and Cmax for darolutamide were 2.5 and 1.6-fold higher in patients with severe renal impairment (estimated Glomerular Filtration Rate [eGFR] 15 to 29 mL/min/1.73 m²) compared to healthy volunteers.
A population pharmacokinetic analysis indicates a 1.1-, 1.3- and an approximately 1.5-fold higher exposure (AUC) of darolutamide in patients with mild, moderate and severe renal impairment (eGFR 15 to 89 mL/min/1.73 m²) compared to patients with normal renal function.
The pharmacokinetics of darolutamide has not been studied in patients with end-stage renal disease receiving dialysis (eGFR <15 mL/min/1.73 m²).
In a clinical pharmacokinetic study, Cmax and AUC for darolutamide were 1.5 and 1.9-fold higher in patients with moderate hepatic impairment (Child-Pugh B) compared to healthy volunteers. There are no data for patients with severe hepatic impairment (Child-Pugh C).
No clinically relevant differences in the pharmacokinetics of darolutamide were observed based on ethnicity (White, Japanese, non-Japanese Asian, Black or African American). A population pharmacokinetic analysis indicated a geometric mean increase in exposure (AUC) of up to 1.56-fold (90% CI: 1.43 to 1.70) in Japanese patients compared to patients from all other regions in both the ARAMIS and ARASENS studies.
In repeated dose toxicity studies in rats and dogs, the main findings were changes in the male reproductive organs (decreases in organ weight with atrophy of the prostate and epididymides). These effects occurred at systemic exposures in the range of or below the anticipated human exposure (based on AUC comparison). Additional changes to reproductive tissues included minimal increase in vacuolation of the pituitary gland, atrophy and secretory reduction in seminal vesicles and mammary glands in rats as well as testicular hypospermia, seminiferous tubule dilatation and degeneration in dogs. Changes in the male reproductive organs in both species were consistent with the pharmacological activity of darolutamide and reversed or partially resolved after 4- to 8-week recovery periods.
Studies on developmental toxicity have not been performed.
Studies on reproductive toxicity have not been performed. However, male fertility is likely to be impaired based on the findings in repeat-dose toxicity studies in rats and dogs, which are consistent with the pharmacological activity of darolutamide.
Darolutamide did not induce mutations in the microbial mutagenesis (Ames) assay. At high concentrations, darolutamide did induce structural chromosome aberrations in vitro in cultured human lymphocytes. However, in the in vivo combined bone marrow micronucleus test and the Comet assay in the liver and duodenum of the rat, no genotoxicity was observed at exposures in excess of the maximum human exposure.
Oral administration of darolutamide to male rasH2 transgenic mice for 6 months did not show carcinogenic potential at doses up to 1000 mg/kg/day, which is 0.9-1.3 times for darolutamide and 2.1-2.3 times for keto-darolutamide the clinical exposure (AUC) at the recommended clinical daily dose of 1200 mg/day. Based on this study carcinogenic risk of darolutamide cannot be completely excluded.
In vitro, darolutamide weakly inhibited the hERG potassium current and the L-type calcium channel. In vivo, in anaesthetised dogs, darolutamide slightly decreased the QT interval duration, but this effect was not found in conscious dogs.
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