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The SARfaris: GPCR, Kinase, ADME

Monday, 13 January 2014

New Drug Approvals 2013 - Pt. XXI - Eslicarbazepine Acetate (AptiomTM)

On November 8th 2013, FDA approved Eslicarbazepine Acetate (tradename: Aptiom; research codes: Sep-0002093, BIA 2-093; ChEMBL: CHEMBL87992), a prodrug indicated as adjunctive treatment of partial-onset seizures associated with epilepsy.

Epilepsy is neurological disorder characterised by abnormal neuronal activity in the brain. Partial-onset seizures, as opposed to generalised seizures, affect initially only one part of the brain and, depending on the part of the brain that is affected, these seizures will present different symptoms.

Eslicarbazepine (ChEMBL: CHEMBL315985), the bioactive ingredient of the prodrug Eslicarbazepine Acetate, exerts its anticonvulsant activity by blocking the voltage-gated sodium channel (VGSC). VGSC has 3 distinctive states: the resting state, during which the VGSC is closed but responsive to a depolarisation impulse, the open state, during which the channel is open allowing the sodium ion to enter the cell, and the inactivated state, in which the channel is closed again but irresponsive to voltage changes. Eslicarbazepine binds and stabilises the inactive form of the VGSC, preventing its reversion to the resting form and limiting sustained repetitive neuronal firing.

VGSC (ChEMBL: CHEMBL2331043) is a single alpha-subunit with four repeat domains each containing six transmembrane segments. A 3D structure of the VGSC in an open conformation (PDBe: 4f4l) is shown below.

Eslicarbazepine Acetate is a synthetic small molecule with a molecular weight of 296.3 g.mol-1, an ALogP of 2.4, 3 hydrogen bond acceptors, 1 hydrogen bond donor, and therefore fully compliant with Lipinski's rule of five.
IUPAC: [(5S)-11-carbamoyl-5,6-dihydrobenzo[b][1]benzazepin-5-yl] acetate
Canonical Smiles: CC(=O)O[C@H]1Cc2ccccc2N(C(=O)N)c3ccccc13
InCHI: InChI=1S/C17H16N2O3/c1-11(20)22-16-10-12-6-2-4-8-14(12)19(17(18)21)15-9-5-3-7-13(15)16/h2-9,16H,10H2,1H3,(H2,18,21)/t16-/m0/s1

The recommended starting dosage of Eslicarbazepine Acetate is 400 mg once daily. After one week, the dosage should be increased to 800 mg once daily (recommended maintenance dosage). The maximum recommended maintenance dosage is 1200 mg once daily (after a minimum of one week at 800 mg once daily).

After oral administration, Eslicarbazepine Acetate is mostly undetectable, since it is extensively and rapidly metabolised by hydrolytic first-pass metabolism to its major active metabolite, Eslicarbazepine, corresponding to 91% of systemic exposure. Eslicarbazepine is highly bioavailable with an apparent volume of distribution of 61L for body weight of 70Kg, a relatively low plasma protein binding (< 40%) and an apparent half-life in plasma of 13-20 hours. Other minor active metabolites of Eslicarbazepine Acetate include (R)-Liscarbazepine and Oxcarbazepine, corresponding to 5% and 1% of systemic exposure, respectively. Eslicarbazepine Acetate metabolites are eliminated mainly by renal excretion, in the unchanged and glucuronide conjugated forms, with Eslicarbazepine and its glucuronide accounting for more than 90% of total metabolites excreted in urine.

The licensed holder of Eslicarbazepine Acetate is Sunovion Pharmaceuticals Inc. and the full prescribing information can be found here.

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