Skip to main content

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

By








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.
Labels:

Comments

Post a Comment

Popular posts from this blog

Improvements in SureChEMBL's chemistry search and adoption of RDKit

By Eloy
    Dear SureChEMBL users, If you frequently rely on our "chemistry search" feature, today brings great news! We’ve recently implemented a major update that makes your search experience faster than ever. What's New? Last week, we upgraded our structure search engine by aligning it with the core code base used in ChEMBL . This update allows SureChEMBL to leverage our FPSim2 Python package , returning results in approximately one second. The similarity search relies on 256-bit RDKit -calculated ECFP4 fingerprints, and a single instance requires approximately 1 GB of RAM to run. SureChEMBL’s FPSim2 file is not currently available for download, but we are considering generating it periodicaly and have created it once for you to try in Google Colab ! For substructure searches, we now also use an RDKit -based solution via SubstructLibrary , which returns results several times faster than our previous implementation. Additionally, structure search results are now sorted by
Post a Comment
Read more

Improved querying for SureChEMBL

By
    Dear SureChEMBL users, Earlier this year we ran a survey to identify what you, the users, would like to see next in SureChEMBL. Thank you for offering your feedback! This gave us the opportunity to have some interesting discussions both internally and externally. While we can't publicly reveal precisely our plans for the coming months (everything will be delivered at the right time), we can at least say that improving the compound structure extraction quality is a priority. Unfortunately, the change won't happen overnight as reprocessing 167 millions patents takes a while. However, the good news is that the new generation of optical chemical structure recognition shows good performance, even for patent images! We hope we can share our results with you soon. So in the meantime, what are we doing? You may have noticed a few changes on the SureChEMBL main page. No more "Beta" flag since we consider the system to be stable enough (it does not mean that you will never
Post a Comment
Read more

ChEMBL brings drug bioactivity data to the Protein Data Bank in Europe

By
In the quest to develop new drugs, understanding the 3D structure of molecules is crucial. Resources like the Protein Data Bank in Europe (PDBe) and the Cambridge Structural Database (CSD) provide these 3D blueprints for many biological molecules. However, researchers also need to know how these molecules interact with their biological target – their bioactivity. ChEMBL is a treasure trove of bioactivity data for countless drug-like molecules. It tells us how strongly a molecule binds to a target, how it affects a biological process, and even how it might be metabolized. But here's the catch: while ChEMBL provides extensive information on a molecule's activity and cross references to other data sources, it doesn't always tell us if a 3D structure is available for a specific drug-target complex. This can be a roadblock for researchers who need that structural information to design effective drugs. Therefore, connecting ChEMBL data with resources like PDBe and CSD is essen
Post a Comment
Read more

ChEMBL 34 is out!

By
We are delighted to announce the release of ChEMBL 34, which includes a full update to drug and clinical candidate drug data. This version of the database, prepared on 28/03/2024 contains:         2,431,025 compounds (of which 2,409,270 have mol files)         3,106,257 compound records (non-unique compounds)         20,772,701 activities         1,644,390 assays         15,598 targets         89,892 documents Data can be downloaded from the ChEMBL FTP site:  https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/ Please see ChEMBL_34 release notes for full details of all changes in this release:  https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_34/chembl_34_release_notes.txt New Data Sources European Medicines Agency (src_id = 66): European Medicines Agency's data correspond to EMA drugs prior to 20 January 2023 (excluding vaccines). 71 out of the 882 newly added EMA drugs are only authorised by EMA, rather than from other regulatory bodies e.g.
Post a Comment
Read more

ChEMBL 26 Released

By
We are pleased to announce the release of ChEMBL_26 This version of the database, prepared on 10/01/2020 contains: 2,425,876 compound records 1,950,765 compounds (of which 1,940,733 have mol files) 15,996,368 activities 1,221,311 assays 13,377 targets 76,076 documents You can query the ChEMBL 26 data online via the ChEMBL Interface and you can also download the data from the ChEMBL FTP site . Please see ChEMBL_26 release notes for full details of all changes in this release. Changes since the last release: * Deposited Data Sets: CO-ADD antimicrobial screening data: Two new data sets have been included from the Community for Open Access Drug Discovery (CO-ADD). These data sets are screening of the NIH NCI Natural Product Set III in the CO-ADD assays (src_id = 40, Document ChEMBL_ID = CHEMBL4296183, DOI = 10.6019/CHEMBL4296183) and screening of the NIH NCI Diversity Set V in the CO-ADD assays (src_id = 40, Document ChEMBL_ID = CHEMBL4296182, DOI = 10.601
Post a Comment
Read more