Indications
Apalutamide is prescribed for the management of specific prostate cancer conditions. Specifically, it is indicated for patients suffering from metastatic castration-sensitive prostate cancer and non-metastatic castration-resistant prostate cancer.
Pharmacodynamics
The pharmacodynamic profile of apalutamide demonstrates a significant affinity for androgen receptors (AR). In particular, studies involving AR-overexpressing LNCaP cells have shown that apalutamide binds to the AR with a 7 to 10-fold greater affinity compared to bicalutamide. Moreover, apalutamide maintains its antagonistic capabilities in cell lines exhibiting bicalutamide-resistant mutations, such as T878A and W741C. Experimental data from castrate mice models possessing LNCaP/AR(cs) tumors indicate that apalutamide induces substantial tumor regression, with a greater than 50% reduction in tumor volume observed in 8 out of 9 mice, compared to only 1 in the bicalutamide group. Additionally, apalutamide-treated tumors displayed a considerable 60% decrease in their proliferative index and a 10-fold increase in apoptosis rates. Moreover, a dedicated QT study in patients with castration-resistant prostate cancer (CRPC) revealed a concentration-dependent prolongation of QTcF with apalutamide and its active metabolite, highlighting its antitumor efficacy in mouse xenograft models by reducing tumor cell proliferation and volume.
Absorption
The absorption characteristics of apalutamide are notable, with a mean absolute oral bioavailability of approximately 100%. After oral administration, peak plasma concentration is typically reached within two hours, although this can range from 1 to 5 hours. At steady-state, following the recommended dosage, the major active metabolite, N-desmethyl apalutamide, exhibits a Cmax of 5.9 mcg/mL and an AUC of 124 mcg·h/mL. Notably, there are no clinically significant differences in Cmax and AUC when apalutamide is administered under fasting conditions compared to a high-fat meal, albeit food intake delays tmax by about 2 hours. Steady-state conditions are usually achieved after four weeks, with a mean accumulation ratio close to five-fold. The fluctuation in daily plasma concentrations is minimal, with a mean peak-to-trough ratio of 1.63. Additionally, dispersing apalutamide tablets in applesauce does not significantly affect its Cmax and AUC compared to intact tablets taken on an empty stomach.
Metabolism
Apalutamide is primarily eliminated through metabolic pathways, predominantly involving the cytochrome P450 enzymes CYP2C8 and CYP3A4, which convert it into its active form, N-desmethyl apalutamide. Following a single dose, the respective contributions of CYP2C8 and CYP3A4 to apalutamide metabolism are estimated to be 58% and 13%. However, at steady-state, these contributions shift to 40% and 37%, respectively. This change is attributed to the auto-induction of CYP3A4, which enhances its enzymatic activity during prolonged apalutamide exposure.
Mechanism of Action
Apalutamide functions as an androgen receptor (AR) antagonist and directly targets the ligand-binding domain of the AR with an IC50 value of 16 nM. In castration-resistant prostate cancer (CRPC), persistent AR signaling is often a result of AR gene amplification, mutations, increased expression, or enhanced androgen biosynthesis within prostate tumors. By binding to the AR, apalutamide effectively disrupts AR signaling, inhibits the binding of AR to DNA, and subsequently impedes AR-mediated gene transcription. Furthermore, it prevents the translocation of AR from the cytoplasm to the nucleus, thereby reducing the availability of AR to interact with androgen response elements (AREs). As a consequence of apalutamide treatment, the recruitment of AR to DNA promoter regions is inhibited. Although its main metabolite, N-desmethyl apalutamide, acts as an AR inhibitor as well, it demonstrates only one-third of the activity of apalutamide in in vitro transcriptional reporter assays.
