Pitolisant

Warning

H361fd (100%): Suspected of damaging fertility; Suspected of damaging the unborn child [Warning Reproductive toxicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

In placebo-controlled trials of pitolisant in patients with narcolepsy, minor serum aminotransferase elevations occurred in a small proportion of patients during therapy, but rates of enzyme elevations were similar to those in placebo recipients. In preregistration trials, there were no instances of clinically apparent liver injury or serum aminotransferase elevations with jaundice attributable to pitolisant. Since its approval in Europe in 2017 and the United States in 2020, there have been no publications describing clinically apparent liver injury due to pitolisant.；Likelihood score: E (unlikely cause of acute liver injury with jaundice).

◉ Summary of Use during Lactation；No information is available on the clinical use of pitolisant during breastfeeding. However, amounts in breastmilk appear to be low and would not be expected to cause any adverse effects in breastfed infants. If pitolisant is required by the mother, it is not a reason to discontinue breastfeeding. Until more safety data are available, pitolisant should be used with careful infant monitoring during breastfeeding.；◉ Effects in Breastfed Infants；Relevant published information was not found as of the revision date.；◉ Effects on Lactation and Breastmilk；Relevant published information was not found as of the revision date.

N - Nervous system；N07 - Other nervous system drugs；N07X - Other nervous system drugs；N07XX - Other nervous system drugs；N07XX11 - Pitolisant

QN - Nervous system；QN07 - Other nervous system drugs；QN07X - Other nervous system drugs；QN07XX - Other nervous system drugs；QN07XX11 - Pitolisant

Pitolisant promotes wakefulness in narcolepsy by enhancing histaminergic signalling in the central nervous system. It does not significantly bind to H1, H2, or H4 receptors. In patients with narcolepsy in presence or absence of cataplexy, treatment of pitolisant was associated with an improvement in the level and duration of wakefulness and daytime alertness assessed by objective measures of ability to sustain wakefulness (e.g. Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) Scores) and attention (e.g. Sustained Attention to Response Task (SART)). Pitolisant also improved the frequency and severity of narcolepsy-associated cataplexy. Pitolisant acts as a blocker at hERG channels. In two QT studies, supra-therapeutic doses of pitolisant (3-6-times the therapeutic dose, that is 108 mg to 216 mg) produced mild to moderate prolongation of QTc interval (10-13 ms).

Signalling of histaminergic neurons plays a key role in activating the arousal system with widespread projections to the whole brain via activating orexin receptors. Narcolepsy is characterized by insufficient neurotransmission by orexins, or hypocretins, which are excitatory peptides released by neurons located from the lateral hypothalamus. These neurons project to aminergic neurons, such as histaminergic or noradrenergic neurons, that are responsible for the effects of orexin and control of wakefulness. Histamine H3 receptors are presynaptic inhibitory autoreceptors that are located in the cerebral cortex, hypothalamus, hippocampus, and basal ganglia. H3 receptors promote the re-uptake of histamine at synaptic terminals and attenuate further histamine release into the synapse. By blocking H3 autoreceptors and increasing the levels of histamine transmitters at the synapse, pitolisant enhances the activity of histaminergic neurons and promotes wakefulness. Inverse agonism of pitolisant at H3 receptors also leads to enhanced synthesis and release of endogenous histamine over the basal level. Pitolisant acts as a high-affinity competitive antagonist (Ki 0.16 nM) and as an inverse agonist (EC50 1.5 nM) at the human H3 receptor and mediates its pharmacological action at the presynaptic level. It is thought to bind to the antagonist binding site of the H3 receptor, which is located within the transmembrane core just below the extracellular loops. Piperidines form a salt bridge with Glu206 in the membrane-spanning segment, and the hydroxyl of Tyr374 is H-bonded with the central oxygen of piperidine. Pitolisant displays high selectivity for H3 receptors compared to other histamine receptor subtypes. Pitolisant also modulates acetylcholine, noradrenaline and dopamine release in the brain by increasing the levels of neurotransmitters but does not increase dopamine release in the stratal complex, including the nucleus accumbens. At lower nanomolar concentrations, pitolisant

Pitolisant is primarily metabolized by CYP2D6 and to a lesser extent by CYP3A4 in the liver. The major non-conjugated metabolites are BP2.941 (piperidine N-oxide) and BP2.951 (5-aminovaleric acid). Metabolites can further undergo conjugation with glycine or glucuronic acid, and oxidation to a minimal extent. Most metabolites of pitolisant do not retain considerable pharmacological activities. Several conjugated metabolites were also identified; the major conjugated inactive metabolite was a glycine conjugate of the acid metabolite of O-dealkylated desaturated pitolisant and a glucuronide of a ketone metabolite of monohydroxy desaturated pitolisant. Due to its extensive metabolism in the liver, the systemic exposure of pitolisant thus adverse events of the drug may be elevated in case of compromised liver function. The dosage adjustments for pitolisant is advised in patients with moderate hepatic impairment.

4BC83L4PIY

PITOLISANT

Established Pharmacologic Class [EPC] - Histamine-3 Receptor Antagonist/Inverse Agonist

Mechanisms of Action [MoA] - Histamine H3 Receptor Inverse Agonists

Mechanisms of Action [MoA] - Histamine H3 Receptor Antagonists

Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inducers

Pitolisant is rapidly and well absorbed following oral administration, resulting in the drug being 90% absorbed. In healthy individuals receiving an oral dose of 20 mg, the Cmax was approximately 30 ng/mL. Following oral administration of pitolisant 35.6 mg once daily, the mean steady state Cmax and AUC were 73 ng/mL and 812 ngxhr/mL, respectively. The Tmax was typically reached approximately 3 hours following administration. Following repeated dosing, the steady-state plasma concentration is achieved after 5-6 days of administration but the inter-individual variability in the time to reach steady-state is reported to be high. The absolute bioavailability of pitolisant has not been determined.

Following hepatic metabolism, about 63% of total elimination occurs via renal excretion into the urine as an inactive non-conjugated metabolite BP2.951 and a glycine conjugated metabolite. About 25% of the total dose administered is excreted through expired air as metabolites, and a small fraction (<3%) of drug can be recovered in faeces.

Following single and multiple oral dosing of pitolisant to healthy male adults at doses between 1 and 240 mg, the apparent volume of distribution (V/F) ranges from 1100 to 2825 L. Pitolisant is thought to be equally distributed between red blood cells and plasma. Following intravenous administration of pitolisant in rats and monkeys, the apparent Vd at steady-state was approximately 10-fold greater than total body water. Pitolisant crosses the blood-brain barrier and placenta, and was found in milk in rats.

The apparent oral clearance (CL/F) of pitolisant was 43.9 L/hr following a single dose of 35.6 mg. The clearance rate is expected to be lower with increasing age.