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New Drug Approvals 2011 - Part XI Gabapentin enacarbil (HorizantTM)

ATC code (partial): N03AX
On April 6th, the FDA approved gabapentin enacarbil (tradename Horizant, Research Code: XP-13512, NDA 022399) for the treatment of moderate-severe forms of restless legs syndrome (RLS).

Patients suffering from RLS experience an urge to move their legs or other limbs. This urge is prompted by a painful or itchy sensation in the corresponding limb. Symptoms are most severe during phases of relaxation. Patients also sometimes have limb jerking during sleep.

Gabapentin enacarbil is a prodrug of the anticonvulsant and analgesic gabapentin (CHEMBL940). Much of the processing of gabapentin enacarbil into the active ingredient takes place in enterocytes, upon absorption in the gut. These first pass modifications are mainly mediated by non-specific carboxylesterases and via several steps of hydrolysis and yield gabapentin (the active ingredient), along with carbon dioxide, acetaldehyde and isobutyric acid. Absorption of Gabapentin into the enterocytes is likely mediated by the monocarboxylate transporter 1 (Uniprot: P53985).

The mechanism of action of gabapentin enacarbil is due entirely to gabapentin, the active component. Gabapentin binds to the a2δ subunit of voltage-gated calcium channels in vitro (Uniprot: Q9NY47). However, it is not fully known how this binding translates into a therapeutic effect. Despite its structural similarity to the neurotransmitter gamma-amino butyric acid (GABA), gabapentin has no effect on the binding, uptake or catabolism of GABA.

Gabapentin enacarbil (Smiles: CC(C(OC(OC(NCC1(CC(O)=O)CCCCC1)=O)C)=O)C, IUPAC: (1-{[({(1RS)-1-[(2-Methylpropanoyl)oxy]ethoxy}carbonyl)amino]methyl} cyclohexyl) acetic acid, InChI: 1S/C16H27NO6/c1-11(2)14(20)22-12(3)23-15(21)17-10-16(9-13(18)19)7-5-4-6-8-16/h11-12H,4-10H2,1-3H3,(H,17,21)(H,18,19), ChemSpider: 8059607) has a molecular weight of 329.39 Da. With two hydrogen bond donors and seven hydrogen bond acceptors and ACD/LogP = 2.66 gabapentin fully complies with the Lipinski rule of five. Gabapentin enacarbil is a racemate, the stereocenter is labelled with an asterisk (in the figure above).

The mean bioavailability of gabapentin enacarbil is 75% in fed state. As for conventional gabapentin, the bioavailability of gabapentin encarbil is lower if administered onto and empty stomach (42-65%).  The TMAX after administration of 600mg of gabapentin enacarbil is ~7h while TMAX for conventional gabapentin is only 2h. Plasma protein binding (ppb) of gabapentin is less than 3% and the volume of distribution is 76 L. The elimination of gabapentin is mainly renal (94% recovered from urine) and renal clearance (CLr) ranges from 5-7 L/hr. While gabapentin enacarbil is extensively processed, the active ingredient gabapentin is not subject to further metabolic modifications. Compared to the parent drug Gabapentin, Gabapentin enacarbil shows an extended release and higher bioavailability. Studies showed no interactions with the major cytochrome P450 enzymes and p-glycoprotein.

The recommended dose for gabapentin enacarbil is 600mg oral, once daily.

The full prescribing information can be found here.

Gabapentin enacarbil is marketed under the name Horizant and was developed by Glaxo Smith Kline and Xenoport.


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