Belinostat

Belinostat is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Belinostat shows preferential cytotoxicity towards tumor cells compared to normal cells. Belinostat inhibited the enzymatic activity of histone deacetylases at nanomolar concentrations (<250 nM).

Cardiac Electrophysiology

Multiple clinical trials have been conducted with belinostat, in many of which ECG data were collected and analyzed by a central laboratory. Analysis of clinical ECG and belinostat plasma concentration data demonstrated no meaningful effect of belinostat on cardiac repolarization. None of the trials showed any clinically relevant changes caused by belinostat on heart rate, PR duration or QRS duration as measures of autonomic state, atrio-ventricular conduction or depolarization; there were no cases of Torsades de Pointes.

The pharmacokinetic characteristics of belinostat were analyzed from pooled data from phase ½ clinical studies that used doses of belinostat ranging from 150 to 1,200 mg/m². The total mean plasma clearance and elimination half-life were 1240 mL/min and 1.1 hours, respectively. The total clearance approximates average hepatic blood flow (1500 mL/min), suggesting high hepatic extraction (clearance being flow dependent).

Distribution

The mean belinostat volume of distribution approaches total body water, indicating that belinostat has limited body tissue distribution. In vitro plasma studies have shown that between 92.9% and 95.8% of belinostat is bound to protein in an equilibrium dialysis assay, and was independent of belinostat plasma concentrations from 500 to 25,000 ng/mL.

Elimination

Metabolism

Belinostat is primarily metabolized by hepatic UGT1A1. Strong UGT1A1 inhibitors are expected to increase exposure to belinostat. Belinostat also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes to form belinostat amide and belinostat acid. The enzymes responsible for the formation of methyl belinostat and 3-(anilinosulfonyl)-benzenecarboxylic acid, (3-ASBA) are not known.

Excretion

Following a single dose of [¹⁴C]-labelled belinostat (100 μCi, 1500 mg) administered as a 30-minute intravenous infusion in patients with recurrent or progressive malignancy (N=6), fecal excretion accounted for a mean (± SD) of 9.7% (± 6.5%) of the administered radioactive belinostat dose over 168 hours. The mean (± SD) of the administered radioactive belinostat dose that was excreted in urine over 168 hours was 84.8% (± 9.8%), of which unchanged belinostat accounted for only 1.7%.

Drug Interaction Studies

In vitro studies showed belinostat and its metabolites (including belinostat glucuronide, belinostat amide, methyl belinostat) inhibited metabolic activities of CYP2C8 and CYP2C9. Other metabolites (3-ASBA and belinostat acid) inhibited CYP2C8.

In cancer patients, co-administration of belinostat (1,000 mg/m²) and warfarin (5 mg), a known CYP2C9 substrate, did not increase the AUC or C_max of either R- or S-warfarin.

Belinostat is likely a glycoprotein (P-gp) substrate but is unlikely to inhibit P-gp.