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Pharmaceuticals -> Antineoplastic and immunomodulating agents -> Antineoplastic agents

Pharmaceuticals -> Listed in ZINC15

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Danger

H360 (94.6%): May damage fertility or the unborn child [Danger Reproductive toxicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 56 reports by companies from 4 notifications to the ECHA C&L Inventory.

In prelicensure controlled trials of apalutamide, serum aminotransferase elevations were uncommon and generally transient and mild, not requiring dose modification. Clinically apparent liver injury with jaundice attributable to apalutamide was not reported in the preregistration trials and is not mentioned as an adverse event in the product label. Since the approval and general clinical use of apalutamide, there have been no publications or descriptions of the clinical features of hepatotoxicity with jaundice associated with its use. The first and second generation androgen receptor blockers, flutamide, nilutamide, and bicalutamide, have all been linked to instances of hepatitis-like liver injury with jaundice that can be severe and even fatal. However, such cases have not been described with apalutamide and other third generation androgen receptor antagonists. Thus, clinically apparent liver injury due to apalutamide must be rare, if it occurs at all.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Apalutamide

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

In androgen receptors (AR)-overexpressing LNCaP cells, apaludatamide was reported to have a 7 to 10-fold greater affinity to the AR than bicalutamide. Additionally, apalutamide still possesses total antagonistic activity in AR-overexpressing cell lines with bicalutamide-resistance mutations such as T878A and W741C. In castrate mice with LNCaP/AR(cs) tumors, apalutamide produced tumor regression (defined by >50% regression in tumor volume) in 8 mice compared to only 1 for bicalutamide. The apalutamide-treated tumors also have a 60% decrease in proliferative index and a 10-fold increase in apoptotic rate compared with vehicle. In an open-label, uncontrolled, multicenter, single-arm dedicated QT study in 45 patients with CRPC, an exposure-QT analysis suggested a concentration-dependent increase in QTcF for apalutamide and its active metabolite. Apalutamide demonstrated antitumor activity in the mouse xenograft models of prostate cancer, where it decreased tumor cell proliferation and reduced tumor volume.

Persistent androgen receptor (AR) signaling is a common feature of castration-resistant prostate cancer (CRPC), attributed to AR gene amplification, AR gene mutation, increased AR expression, or increased androgen biosynthesis in prostate tumors. Apalutamide is an antagonist of AR that binds directly to the ligand-binding domain of the AR with the IC50 of 16 nM. Upon binding, apalutamide disrupts AR signalling, inhibits DNA binding, and impedes AR-mediated gene transcription. Apalutamide impairs the translocation of AR from the cytoplasm to the nucleus thus reducing the concentrations of AR available to interact with the androgen response elements (AREs). Upon treatment with apalutamide, AR was not recruited to the DNA promoter regions. Its main metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third of the activity of apalutamide in an in vitro transcriptional reporter assay.