The effect of food on the bioavailability of panobinostat, an orally active pan-histone deacetylase inhibitor, in patients with advanced cancer

Abstract

Purpose Panobinostat is a novel oral pan-deacetylase inhibitor with promising anti-cancer activity. The study aimed to determine the influence of food on the oral bioavailability of panobinostat. Methods This multicenter study consisted of a randomized, three-way crossover, food-effect study period (cycle 1) followed by single-agent panobinostat continual treatment phase in patients with advanced cancer. Patients received panobinostat 20 mg twice weekly, and panobinostat pharmacokinetics was investigated on days 1, 8, and 15 with a randomly assigned sequence of three prandial states (fasting, high-fat, and normal breakfast). Results Thirty-six patients were assessed for the food effect on pharmacokinetics and safety in cycle 1, after which 29 patients continued treatment, receiving singleagent panobinostat. Safety and antitumor activity were assessed during the extension period. Panobinostat systemic exposure was marginally reduced (14–16%) following food [geometric mean ratio (GMR) of the AUC0–∞/high-fat breakfast/fasting, 0.84 (90% confidence interval {CI}, 0.74–0.96); normal breakfast/fasting, 0.86 (90% CI, 0.75–1.00)], and interpatient variability (coefficient of variation, 59%) remained essentially unchanged with or without food. Panobinostat Cmax was reduced by 44% (high-fat) and 36% (normal) with median Tmax prolonged by 1–1.5 h following food. Panobinostat was well tolerated, with thrombocytopenia, fatigue, nausea, and vomiting as common adverse events, and demonstrated antitumor activity with one patient with a partial response and six patients with stable disease as best response. Conclusions Food produced minor changes in oral panobinostat exposure; thus, panobinostat can be given without regard to food intake in future clinical studies.

Functional and Transcriptional Characterization of Histone Deacetylase Inhibitor-Mediated Cardiac Adverse Effects in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…Figure 1 shows impedance tracings of cardiomyocytes at 6, 24, and 72 hours after dose using concentrations around the free (unbound) peak therapeutic plasma concentration ( C eff ) and approximately 10‐fold higher. C eff values were based on current dosing schedules for panobinostat [19], vorinostat [20], and entinostat [18], whereas for dacinostat, we used the plasma concentration associated with dose‐limiting toxicities [10]. Within 6 hours, none of the HDAC inhibitors altered the beating pattern of cardiomyocytes, suggesting no acute effects.…”

A Proposal Regarding Reporting of In Vitro Testing Results

“…Panobinostat, which was described as a “broadly active compound” in a report describing the CancerCell Line Encyclopedia, showed an IC 50 of approximately 60 nM against the approximately 500 cell lines against which it was tested (30). However, at the commonly used dose and schedule of this agent (20 mg administered orally 2-3 times per week), C max values are only in the 40- 70 nM range (40-42), and concentrations above 15 nM are maintained for less than 12 hours out of every 48 hour dosing interval (40). Of note, in vitro exposure to panobinostat for 12 hours or less produces limited in vitro effects (39).…”

Panobinostat: First Global Approval

“…Panobinostat exposure is approximately dose proportional over the dosing range, and it has an absolute oral bioavailability of 21 % [6]. Following a high-fat meal in patients with advanced cancer, panobinostat exposure was decreased slightly compared with fasting conditions, and the time to C max (t max ) was increased by 2.5 h [19]. With chronic oral dosing, up to 2-fold accumulation was observed in patients with advanced cancer [6].…”