Chemical formula: C₂₄H₂₇N₃O₄ Molecular mass: 421.2 g/mol PubChem compound: 9804992
Givinostat is a class I and II histone deacetylase (HDAC) inhibitor that modulates the uncontrolled HDAC activity in dystrophic muscles, which contributes to the pathology of Duchenne muscular dystrophy (DMD).
Givinostat HDAC inhibition has been shown to reduce muscle fiber damage, chronic muscular inflammation, fibrosis, fat deposition, and to promote mitochondrial biogenesis.
Givinostat mechanism of action is independent of the underlying dystrophin gene mutation causing the disease.
The percentage of fat fraction present in the vastus lateralis muscles (VLM) of the thigh was measured in EPIDYS Study using magnetic resonance spectroscopy. At 18 months, for the patients with baseline VLM fat fraction in the range of >5% to ≤30%, a LS mean increase of VLM fat fraction was 7.63% in the givinostat-treated patients compared to a 10.56% increase in patients who received placebo.
Givinostat is well absorbed after oral administration. Mean plasma concentrations increase in a dose-proportional manner, and maximum plasma concentrations are achieved about 2-3 hours after administration. A high fat standard meal resulted in some increase in the exposure (about 30% increase in area under the plasma concentration-time curve [AUC] and about 20% increase in maximum plasma concentration [Cmax]) and a delay in time to maximum concentration (Tmax) from 2 to 3 hours. Steady-state concentrations are achieved within 5 to 7 days after both once a day and twice a day dosing. A moderate accumulation of less than 2-fold was observed after twice daily administration.
A physiologically based pharmacokinetic analysis, including healthy volunteer data, predicted an oral bioavailability in humans ≥50% after single oral administration at the dose range of 44.3 to 177.2 mg.
Givinostat is approximately 96% bound to human plasma proteins and is slightly partitioned into red blood cells (blood to plasma ratio = 1.3).
In vitro studies with human enzymatic preparations together with animal metabolism in vitro and in vivo showed that givinostat is extensively metabolised forming several metabolites. CYP450 and UGTs are not involved in the main metabolic reactions. The enzymes forming the primary metabolites have only been partially identified. Four major metabolites, which are inactive, have been characterized in humans and animal species, although with differences in quantitative amounts.
In plasma, givinostat displays a bi-phasic elimination profile with a mean apparent terminal elimination phase (half-life) of about 6 hours. The elimination of givinostat is likely dependent on metabolism followed by renal and biliary excretion. Urinary excretion of givinostat and the main metabolites in humans has been evaluated in healthy volunteers after single and repeated doses of givinostat. The percentage of unchanged givinostat recovered in urine was very low after both single and repeated twice daily administration (<3% of the dose).
The pharmacokinetics of givinostat is linear, since the AUC∞ obtained after single administration is comparable to that with repeated once daily administration, with a possible minimal apparent accumulation of active substance over time (range of accumulation ratios found 1.0-1.7). Linearity was tested after single administration of doses 44.3 to 354.4 mg and multiple administration of doses 44.3 to 177.2 mg.
Based on the population PK analyses, weight resulted to significantly affect givinostat clearance. The effect is not linear, i.e., the effect is larger at smaller weights and smaller in weights 30 kg and above. Thus, a weight-based dose is recommended.
The population PK analyses show that age or co-administration with corticosteroids has no effects on the pharmacokinetics of givinostat. The pharmacokinetics of givinostat have been evaluated in male paediatric DMD patients from 6 years old.
Givinostat has not been studied in patients with hepatic impairment. Caution should be exercised in the administration and monitoring of the product in these patients.
Givinostat has not been studied in patients with renal impairment. However, renal impairment is not expected to impact the exposure of givinostat because renal excretion is not a significant route of givinostat elimination.
In repeated dose oral toxicity studies in rats and monkeys, a dose dependent decrease in white blood counts with related atrophy of lymphoid organs (thymus, lymph nodes and spleen), in red blood cell and platelet counts, and in cellularity in the bone marrow was seen with givinostat. An increase in liver enzymes was also observed. In monkeys, bile duct hyperplasia was additionally induced. These toxicities were generally reversible upon drug discontinuation, but developed at lower givinostat exposures in animals than achieved at the maximum recommended human dose (MRHD).
Givinostat was positive for frameshift mutations at high doses in vitro in bacteria (Ames test), negative in mammalian cells (TK+/- in mouse lymphoma cells), and negative in vivo in transgenic BigBlue rats and in the Pig-a locus.
In conclusion givinostat does not pose a relevant genotoxic potential in vivo.
No data from carcinogenicity studies with givinostat are currently available.
Givinostat caused dose-dependent decreases in size and weight of male accessory organs already starting at the lowest dose. Mid and high dose animals showed an increase of the pre-coital interval and lower amounts of copulation plugs probably resulting from disturbance on ejaculate formation. However, sperm parameters and number of pregnant females were not affected.
Maternal adverse effects were observed at the high dose levels in the embryo-foetal and in the pre- and postnatal development toxicity studies. Effects on gestation, embryo-foetal development and litter parameters were considered secondary to maternal toxicity. However, effects on embryo-fetal development and litter parameters were already observed at mid dose levels in the rat and rabbit embryo-fetal development study as well as in the low dose group of the pre-/postnatal development study. There was no adverse effect on offspring behaviour, neurological growth, sexual maturation and reproductive function.
Overall, effects on reproductive toxicity were observed at lower givinostat exposures in animals than achieved at the MRHD, except for the embryo-foetal development study in rabbits with a safety margin of about 10 towards human exposure at the MRHD.
In rats, some effects were observed on haematological parameters and lymphoid organs at the high dose levels, which were fully or partially reversible. These effects were observed at lower givinostat exposures in animals than achieved at the MRHD. No treatment-related effects on animal growth, sexual maturation, reproductive performances, and in neurobehavioural development were observed.
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