Pharmacodynamics Antiandrogenic activity<unk>  acts as a selective competitive silent antagonist of the androgen receptor (AR), via the ligand-binding domain, and hence is an antiandrogen. It is similar both structurally and pharmacologically to the second-generation NSAA enzalutamide, but shows some advantages, including higher antiandrogenic activity as well as several-fold reduced central nervous system distribution. The latter difference may reduce its comparative risk of seizures and other central side effects.<unk>  has 5- to 10-fold greater affinity for the AR than bicalutamide, a first-generation NSAA. The acquired F876L mutation of the AR identified in advanced prostate cancer cells has been found to confer resistance to both enzalutamide and<unk> . A newer NSAA, darolutamide, is not affected by this mutation, nor has it been found to be affected by any other tested/well-known AR mutations.<unk>  may be effective in a subset of prostate cancer patients with acquired resistance to abiraterone acetate. Other activities<unk>  shows potent induction potential of cytochrome P450 enzymes similarly to enzalutamide. It is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9, as well as an inducer of UDP-glucuronosyltransferase. In addition,<unk>  is an inducer of P-glycoprotein, ABCG2, and OATP1B1.<unk>  binds weakly to and inhibits the GABAA receptor in vitro similarly to enzalutamide ( = 3.0 and 2.7 μM, respectively), but due to its relatively lower central concentrations, may have a lower risk of seizures in comparison.<unk>  has been found to significantly and concentration-dependently increase QT interval. Pharmacokinetics The mean absolute oral bioavailability of<unk>  is 100%. Mean peak levels of<unk>  occur 2 hours following administration, with a range of 1 to 5 hours. Food delays the median time to peak levels of<unk>  by approximately 2 hours, with no significant changes in the peak levels themselves or in area-under-curve levels. Steady-state levels of<unk>  are achieved following 4 weeks of administration, with an approximate 5-fold accumulation. Peak concentrations for 160 mg/day<unk>  at steady-state are 6.0 μg/mL (12.5 μmol/L), relative to peak levels of 16.6 μg/mL (35.7 μmol/L) for 160 mg/day enzalutamide and mean (R)-bicalutamide levels of 21.6 μg/mL (50.2 μmol/L) for 150 mg/day bicalutamide. The mean volume of distribution of<unk>  at steady-state is approximately 276 L. The plasma protein binding of<unk>  is 96%, while that of its major metabolite N-desmethylapalutamide is 95%, both irrespective of concentration.<unk>  is metabolized in the liver by CYP2C8 and CYP3A4. A major active metabolite, N-desmethylapalutamide, is formed by these enzymes, with similar contribution of each of these enzymes to its formation at steady-state. Following a single oral dose of 200 mg<unk> ,<unk>  represented 45% and N-desmethylapalutamide 44% of total area-under-curve levels. The mean elimination half-life of<unk>  at steady-state is 3 to 4 days. Fluctuations in<unk>  exposure are low and levels are stable throughout the day, with mean peak-to-trough ratios of 1.63 for<unk>  and 1.27–1.3 for N-desmethylapalutamide. After a single dose of<unk> , its clearance rate (CL/F) was 1.3 L/h, while its clearance rate increased to 2.0 L/h at steady-state. This change is considered to be likely due to CYP3A4 auto-induction. Approximately 65% of<unk>  is excreted in urine (1.2% as unchanged<unk>  and 2.7% as N-desmethylapalutamide) while 24% is excreted in feces (1.5% as unchanged apalutmaide and 2% as N-desmethylapalutamide).
Apalutamide
Darolutamide
Bicalutamide
Nilutamide
Acetothiolutamide
Topilutamide
Flutamide
Enzalutamide