FDA Approves XCOPRI for Partial-Onset Seizures in Adult Patients

The U.S. Food and Drug Administration (FDA) approved XCOPRI (cenobamate) for the treatment of partial-onset seizures in adult patients. The approved recommended dosage of XCOPRI is 12.5 mg orally once daily, titrated to the recommended maintenance dosage of 200 mg orally once daily. The maximum dosage is 400 mg orally once daily. The recommended dosage and titration should not be exceeded because of the potential for serious adverse reactions. If XCOPRI is discontinued, the dosage should be gradually reduced over a period of at least 2 weeks, unless safety concerns require abrupt withdrawal.

XCOPRI is contraindicated in patients with hypersensitivity to cenobamate or any of the inactive ingredients in XCOPRI or with familial short QT syndrome. Caution should be used when administering XCOPRI and other drugs that shorten the QT interval. Concomitant use of XCOPRI with other CNS depressants, including alcohol, may have additive effects. Additional information regarding dosage and administration as well as important warnings and precautions related drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity, QT shortening, suicidal behavior and ideation, neurological adverse reactions, and withdrawal of antiepileptic drugs can be found in the full prescribing information linked below.

The precise mechanism by which cenobamate exerts its therapeutic effects in patients with partial-onset seizures is unknown. Cenobamate reduces repetitive neuronal firing by inhibiting voltage-gated sodium currents and is a positive allosteric modulator of the γ-aminobutyric acid (GABAA) ion channel.

Cenobamate AUC increases in a greater than dose-proportional manner following single doses from 5 to 750 mg (0.0125 to 1.88 times the approved maximum recommended dosage). Cenobamate Cmax increases in a dose proportional manner. Steady-state plasma concentrations are attained after approximately two weeks of once daily dosing.

At least 88% of XCOPRI is absorbed following oral administration, with median Tmax ranging from 1 to 4 hours.

The apparent volume of distribution of cenobamate is approximately 40-50 L. Plasma protein binding is 60%, primarily to human albumin, and independent of concentration in vitro.

The apparent terminal half-life of cenobamate is 50-60 hours and apparent oral clearance is approximately 0.45-0.63 L/hour over a dose range from 100 mg/day to 400 mg/day.

Cenobamate undergoes glucuronidation via UGT2B7 and to a lesser extent by UGT2B4, and oxidation via CYP2E1, CYP2A6, CYP2B6 and to a lesser extent by CYP2C19 and CYP3A4/5. Following administration of radiolabeled cenobamate, unchanged cenobamate accounted for > 98% of the total AUC of radioactivity in plasma.

Following administration of radiolabeled cenobamate, a mean of 87.8% of the total dose was recovered in urine and 5.2% in feces. Unchanged cenobamate accounted for 6.8% of the dose which was mainly excreted in the urine (6.4%). More than 50% of the radioactivity was excreted within 72 hours of dosing.

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 XCOPRI 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 XCOPRI. 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 XCOPRI-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.

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