SUMMARY

• There are no published studies in humans describing the ability of ERLEADA to cross the blood-brain barrier.
• In a plasma and brain tissue distribution study conducted in mice, the mean steadystate apalutamide brain levels were 4-fold lower than those observed for enzalutamide (0.479±0.132 μg/g and 2.01±0.83 μg/g, respectively).¹
• In a gamma-aminobutyric acid (GABA_A)-binding experiment conducted in rats, apalutamide and enzalutamide exhibited low micromolar affinity for the GABA_A receptor in radioligand binding assays (half maximal inhibitory concentration [IC₅₀] 3.0 μmol/L and 2.7 μmol/L, respectively).¹
• Preclinical data comparing apalutamide, darolutamide, and enzalutamide tissue distribution and brain concentrations in rodents have also been reported.^2,3

BACKGROUND

In in vitro studies, androgen receptor (AR) inhibitors have been shown to inhibit the GABA_A receptor, a mechanism that is associated with inducing seizures.⁴ Thus, the degree of permeability of the blood-brain barrier to AR inhibitors may be a further determinant of seizure risk.¹ There are no published studies in humans describing the ability of ERLEADA to cross the blood-brain barrier; however, a preclinical study evaluating apalutamide brain concentrations and GABA_A-binding affinity was conducted in rodents.¹

CLINICAL DATA

No studies have been conducted in humans to evaluate the concentration of apalutamide in brain tissue or the central nervous system.

PRECLINICAL DATA

Steady State Brain/Plasma Levels in Mice and GABA_A-Binding Affinities in Rats

Clegg et al (2012)¹ compared apalutamide and enzalutamide steady-state plasma and brain levels in mice and GABA_A-binding affinities in rats as part of the preclinical development program for apalutamide.

Study Design/Methods

• Mice were given a dose of either apalutamide or enzalutamide 10 mg/kg/day for 28 days, and brain and plasma drug levels were measured 24 hours after the final dose (C_24h).
• Brain tissue distribution was quantified by liquid chromatography/tandem mass spectrometry (LC-MS/MS).
• GABA_A-binding experiments in membrane homogenates of rat cerebral cortex used [³⁵S]TBPS competitor with picrotoxin as a positive control.

Results

Steady-State Plasma and Brain Concentrations in Mice

• A total of 8 mice received apalutamide, and 5 mice received enzalutamide.
• Apalutamide brain levels at steady state were 4-fold lower than those observed for enzalutamide (Table: Apalutamide and Enzalutamide Steady-State Levels in Plasma and Brain Tissue of Mice).

GABA_A-binding Affinities in Rats

• Apalutamide and enzalutamide exhibited low micromolar affinity for the GABA_A receptor in radioligand binding assays (IC₅₀ 3.0 μmol/L and 2.7 μmol/L, respectively).

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 09 September 2024.