Chemical formula: C₂₁H₂₃N₃O₂ Molecular mass: 349.434 g/mol PubChem compound: 6918837
Panobinostat is a histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDACs at nanomolar concentrations. HDACs catalyse the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. Inhibition of HDAC activity results in increased acetylation of histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation. In vitro, panobinostat caused the accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. Increased levels of acetylated histones were observed in xenografts from mice that were treated with panobinostat. Panobinostat shows more cytotoxicity towards tumour cells compared to normal cells.
Treatment of tumour cells with panobinostat resulted in a dose-dependent increase in acetylation of histones H3 and H4 both in vitro and in xenograft animal pre-clinical models, demonstrating target inhibition. In addition, increased expression of the tumour suppressor gene p21CDKNIA (cyclin dependent kinase inhibitor 1/p21) gene, a key mediator of G1 arrest and differentiation, was triggered with panobinostat exposure.
Panobinostat is rapidly and almost completely absorbed with T max reached within 2 hours of oral administration in patients with advanced cancer. The absolute oral bioavailability of panobinostat was approximately 21%. After oral administration, panobinostat pharmacokinetics appear to be linear in the dose range 10-30 mg, but AUC increases less than proportionally with dose at higher doses.
Overall panobinostat exposure and inter-patient variability remained unchanged with or without food, whereas Cmax was reduced by <45% and Tmax prolonged by 1 to 2.5 hours with food (i.e. both normal and high-fat breakfasts). Since food did not alter overall bioavailability (AUC), panobinostat can be administered regardless of food in cancer patients.
Panobinostat is moderately (approximately 90%) bound to human plasma proteins. Its fraction in the erythrocyte is 0.60 in vitro, independent of the concentration. The volume of distribution of panobinostat at steady state (Vss) is approximately 1,000 litres based on final parameter estimates in the population pharmacokinetic analysis.
Panobinostat is extensively metabolised, and a large fraction of the dose is metabolised before reaching the systemic circulation. Pertinent metabolic pathways involved in the biotransformation of panobinostat are reduction, hydrolysis, oxidation and glucuronidation processes. Oxidative metabolism of panobinostat played a less prominent role, with approximately 40% of the dose eliminated by this pathway. Cytochrome P450 3A4 (CYP3A4) is the main oxidation enzyme, with potential minor involvement of CYP2D6 and 2C19.
Panobinostat represented 6 to 9% of the drug-related exposure in plasma. The parent substance is deemed to be responsible for the overall pharmacological activity of panobinostat.
After a single oral dose of [14C] panobinostat in patients, 29 to 51% of administered radioactivity is excreted in the urine and 44 to 77% in the faeces. Unchanged panobinostat accounted for <2.5% of the dose in urine and <3.5% of the dose in faeces. The remainders are metabolites. Apparent panobinostat renal clearance (CLR/F) was found to range from 2.4 to 5.5 l/h. Panobinostat has a terminal elimination half-life of approximately 37 hours based on final parameters estimate in the population PK analysis.
Panobinostat was not evaluated in multiple myeloma patients under 18 years of age.
In the phase III clinical study 162 out of 387 patients were aged 65 years or over. Plasma exposure of panobinostat in patients aged 65 years or younger was similar to those older than 65 years in the pooling of single-agent panobinostat studies between the dose range of 10 mg and 80 mg.
The effect of hepatic impairment on the pharmacokinetics of panobinostat was evaluated in a phase I study, in 24 patients with solid tumours and with varying degrees of hepatic impairment. Mild and moderate hepatic impairment as per NCI-CTEP classification increased panobinostat plasma exposure by 43% and 105%, respectively. No pharmacokinetic data are available for patients with severe hepatic impairment.
The effect of renal impairment on the pharmacokinetics of panobinostat was assessed in a phase I study in 37 patients with advanced solid tumours with varying degrees of renal function. Mild, moderate and severe renal impairment based on baseline urinary creatinine clearance did not increase the panobinostat plasma exposure in mild, moderate and severe groups.
The primary target organs of toxicity following administration of panobinostat in rats and dogs were identified as the erythropoietic, myelopoietic and lymphatic systems. The thyroid changes including hormones in dogs (decrease triodothyronine (T3)) and rats (decrease in triodothyronine (T3), tetraiodothyronine (T4) (males) and thyroid stimulating hormone (TSH)) were observed at exposures corresponding to 0.07-2.2 of the human AUC observed clinically.
Carcinogenicity studies have not been performed with panobinostat. Panobinostat has demonstrated mutagenic potential in the Ames assay, endo-reduplication effects in human peripheral blood lymphocytes in vitro, and DNA damage in an in vivo COMET study in mouse lymphoma L5178Y cells, that are attributed to the pharmacological mode of action.
An increase in early resorptions was observed in female rats (doses ≥30 mg/kg). Prostatic atrophy accompanied by reduced secretory granules, testicular degeneration, oligospermia and increased epididymal debris were observed in dogs at exposures corresponding to 0.41-0.69 of the human clinical AUC and not fully reversible after a 4 week recovery period.
Based on animal data, the likelihood of panobinostat increasing the risk of foetal death and developmental skeletal abnormalities is predicted to be high. Embryo foetal lethality and increases in skeletal anomalies (extra sternabrae, extra ribs, increases in minor skeletal variations, delayed ossification and variations of the sternabrae) were seen above exposures corresponding to 0.25 of the human clinical AUC.
The effects of panobinostat on labour and post-natal growth and maturation were not evaluated in animal studies.
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