Chemical formula: C₁₀H₁₀ClN₅O₂ Molecular mass: 267.67 g/mol
Cenobamate is a small molecule with a dual mechanism of action. It is a positive allosteric modulator of subtypes of the γ-aminobutyric acid (GABAA) ion channel, that does not bind to the benzodiazepine binding site. Cenobamate has also been shown to reduce repetitive neuronal firing by enhancing the inactivation of sodium channels and by inhibiting the persistent component of the sodium current. The precise mechanism of action by which cenobamate exercises its therapeutic effectsin patients with focalonset seizures is unknown.
No clinically significant differences on objective attention, psychomotor performance, and memory tests, in addition to other subjective CNS tests, were observed following concomitant use of cenobamate and ethanol (preparation of 40% ethanol in orange juice dosed at 0.7 g/kg for males and 0.57 g/kg for females) in healthy subjects.
In a placebo-controlled QT study in healthy volunteers, dose-dependent shortening of the QTcF interval has been observed with cenobamate. The mean ΔΔQTc is -11 [-13, -8] msec for 200 mg once daily and -18 [-22, -15] msec for 500 mg once daily (1.25 times the maximum recommended dosage). A higher percentage of cenobamate-treated subjects (31% at 200 mg and 66% at 500 mg) had a QT shortening of greater than 20 msec compared to placebo (6-17%). Reductions of the QTc interval below 300 msec were not observed.
Cenobamate is well absorbed (at least 88% based on urine recovery) after oral administration, with median Tmax ranging from 1 to 4 hours after single- or multiple-dose administration under fasted condition over the range of 10 to 400 mg. Co-administration with a high-fat meal (800-1,000 kcal with 50% fat) showed no significant effect on the rate and the extent of absorption of cenobamate.
The apparent volume of distribution (Vd/F) of cenobamate after oral administration is approximately 40-50 L. Plasma protein binding of cenobamate is 60% and independent of concentration in vitro. Cenobamate primarily binds with human albumin protein.
Cenobamate is extensively metabolised. The primary metabolic pathway is glucuronidation via UGT2B7 and to a lesser extent by UGT2B4. Minor pathways for metabolism of cenobamate include oxidation via CYP2E1, CYP2A6, CYP2B6, and to a lesser extent by CYP2C19 and CYP3A4/5.
Cenobamate and its metabolites are eliminated primarily via urine. Excretion via faeces accounted for only 5.2% of the dose. More than 50% of the dose was excreted within 72 hours. The apparent terminal half-life of cenobamate in plasma was 50-60 hours within the therapeutic range of 100 mg/day to 400 mg/day. Steady state is reached by 14 days.
The Cmax of cenobamate increased proportionally with increasing doses following single oral doses from 5 to 750 mg and multiple oral doses from 50 to 500 mg/day. Steady-state exposures (Cmax and AUC) increased proportionally with increasing doses in the therapeutic range (100 to 400 mg), but doses less than 100 mg/day may be cleared faster.
Cenobamate plasma AUC was 1.4-fold to 1.5-fold higher in subjects with mild (CLcr 60 to <90 mL/min) and moderate (CLcr 30 to <60 mL/min) renal impairment following a single oral 200 mg dose of cenobamate compared to healthy controls. In subjects with severe (CLcr <30 mL/min) renal impairment, cenobamate plasma AUC did not change significantly compared to healthy controls following single oral 100 mg dose of cenobamate, The effect of haemodialysis on cenobamate pharmacokinetics has not been studied.
Cenobamate plasma AUC was 1.9-fold and 2.3-fold higher in subjects with mild and moderate hepatic impairment, respectively, following a single oral 200 mg dose of cenobamate compared to matched healthy controls The effect of severe hepatic impairment on cenobamate pharmacokinetics has not been studied.
There was no difference observed in the pharmacokinetics of cenobamate between male and female patients.
No clinically significant effect of ethnicity on the pharmacokinetics of cenobamate was noted in a population PK analysis of pooled data from clinical studies from subjects categorised as Asian, Black, Caucasian, Hispanic or other.
A 45% decrease in exposure has been estimated across a body weight range from 54 kg to 112 kg. This variability is not considered to be clinically relevant when establishing a dose of cenobamate. However, cenobamate dose adjustments may need to be considered in patients who experience weight changes of ≥30% of their initial body weight, or more.
No clinically significant differences in the pharmacokinetics of cenobamate were observed based on age based on data from subjects aged 18 years to 77 years.
Safety and effectiveness of cenobamate in patients less than 18 years of age has not been established.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, and carcinogenic potential. However, maximum systemic exposure achieved in the carcinogenicity study in rats was less than that in humans at the maximum recommended human dose (MRHD) of 400 mg/day.
Maximum doses in repeat dose toxicity studies were limited by the exaggerated CNS effects of cenobamate (including hypoactivity, uncoordinated gait, hypothermia, and tremor). Systemic exposures at NOAEL (no observed adverse effect levels) were identified or below exposures reached in humans at the MRHD.
Reproductive toxicity studies showed adverse effects on embryo-foetal and postnatal development. No adverse effects were observed on fertility. However, systemic exposures at the respective NOAELs for the fertility, embryo-foetal development and pre-postnatal development were bellow human exposure at the MRHD.
Administration of cenobamate to pregnant rats and rabbits during the period of organogenesis resulted in increased embryo-foetal mortality, at dose levels associated with maternal toxicity. In rats, there was a small increase in visceral malformations at the high dose; however full interpretation of the teratogenic potential at the high dose was not possible due to the high maternal toxicity.
When cenobamate was administered to female rats throughout pregnancy and lactation, neurobehavioural impairment (increased auditory startle response) was observed in the offspring at all doses and decreased preweaning body weight gain and adverse reactions on female reproductive function (decreased numbers of corpora lutea, implantations and live foetuses) were seen in the offspring
Placental and lacteal transfer of cenobamate was confirmed by the presence of cenobamate in both amniotic fluid and foetal blood from pregnant rats and in the milk of lactating rats.
The environmental risk assessment demonstrated that cenobamate is very persistent (vP) in aquatic systems.
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