Skip to main content

New Drug Approvals 2011 - Pt. XXVIII Clobazam (OnfiTM)







ATC Code: N05BA09
Wikipedia: Clobazam

On October 24th, the FDA approved Clobazam (Tradename: OnfiTM; Research Code: RU-4723), a GABAA receptor agonist, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged two years or older.

Lenox-Gastaut syndrome is a rare and severe form of epilepsy that is typically diagnosed in childhood and often persists into adulthood. LGS accounts for 1-4% of childhood epilepsies, and it is associated with multiple types of seizures, as well as, daily periods of frequent seizures.

Clobazam decreases the frequency of the LGS seizures by potentiating GABAergic neurotransmission, trough the binding of the GABAA receptor at the benzodiazepine site.

GABAA receptor is a protein complex of five subunits (mainly α2β2γ) located in the synapses of neurons. All GABAA receptors contain an ion channel that conducts chloride ions across neuronal cell membranes and two binding sites for the neurotransmitter GABA, while a subset of GABAA receptor complexes also contain a single binding site for benzodiazepines, also referred to as benzodiazepine receptors (BzR). Benzodiazepines, like clobazam, bind at the interface of the α and γ subunits on the GABAA receptor. Once bound to the benzodiazepine receptor, the benzodiazepine ligand locks the benzodiazepine receptor into a conformation in which it has a greater affinity for the GABA neurotransmitter. This increases the frequency of the opening of the associated chloride ion channel and hyperpolarizes the membrane of the associated neuron. The inhibitory effect of the available GABA is potentiated, leading to sedatory and anxiolytic effects.


Clobazam (IUPAC: 7-chloro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4-dione; SMILES: CN1C(=O)CC(=O)N(c2ccccc2)c3cc(Cl)ccc13; PubChem: 2789; Chemspider: 2687; ChEMBLID: CHEMBL70418; Standard InChI Key: CXOXHMZGEKVPMT-UHFFFAOYSA-N) has a molecular weight of 300.7 Da, two hydrogen bond acceptors, no hydrogen bond donors, and has an ALogP of 2.74. Clobazam is a benzodiazepine derivative, a large and well established class of pharmacologically active compounds. So far, it is the only marketed 1,5-benzodiazenpine, being prefered over the 1,4-benzodiazepines already in the market: clonazepam and nitrazepam.

Clobazam is available as oral tablets of 5, 10 and 20mg, and the recommend daily dose is twice the amount of the tablets according to body weight. It has an apparent volume of distribution of 100L at steady state, and its relative bioavailability compared to an oral solution is 100%. The major metabolite of Clobazam is N-desmethylclobazam, which has about 1/5 of the activity of clobazam. Both compounds bind to human plasma proteins (80-90% and 70% respectively). The estimated mean elimination half-life (t1/2) is approximately 36-42 hr for clobazam and 71-82 hr for the active metabolite.

Clobazam is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. In vitro metabolism studies demonstrate that clobazam and its active metabolite induce CYP3A4 activity in a concentration-dependent manner. N-desmethylclobazam is extensively metabolised by the polymorphic CYP2C19, therefore, dosage in patients who are known CYP2C19 poor metabolisers may need to be adjusted. For further drug-drug interactions please refer to the full prescribing information.

Clobazam has been granted an orphan drug designation because it is intended to treat a condition that affects fewer than 200,000 people.

The license holder for OnfiTM is Lundbeck, and the full prescribing information can be found here.

Although clobazam has just been approved in the United States, it has been marketed outside of the US for several years under various brand names, including Frisium® and Urbanyl®, both licensed by Sanofi-Aventis. A full list of brand names can be found here.

Comments

Small type: The main GABAA composition in the mammal brain is α1-β2-γ2.

Popular posts from this blog

A python client for accessing ChEMBL web services

Motivation The CheMBL Web Services provide simple reliable programmatic access to the data stored in ChEMBL database. RESTful API approaches are quite easy to master in most languages but still require writing a few lines of code. Additionally, it can be a challenging task to write a nontrivial application using REST without any examples. These factors were the motivation for us to write a small client library for accessing web services from Python. Why Python? We choose this language because Python has become extremely popular (and still growing in use) in scientific applications; there are several Open Source chemical toolkits available in this language, and so the wealth of ChEMBL resources and functionality of those toolkits can be easily combined. Moreover, Python is a very web-friendly language and we wanted to show how easy complex resource acquisition can be expressed in Python. Reinventing the wheel? There are already some libraries providing access to ChEMBL d

ChEMBL 29 Released

  We are pleased to announce the release of ChEMBL 29. This version of the database, prepared on 01/07/2021 contains: 2,703,543 compound records 2,105,464 compounds (of which 2,084,724 have mol files) 18,635,916 activities 1,383,553 assays 14,554 targets 81,544 documents Data can be downloaded from the ChEMBL FTP site:   https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_29 .  Please see ChEMBL_29 release notes for full details of all changes in this release: https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_29/chembl_29_release_notes.txt New Deposited Datasets EUbOPEN Chemogenomic Library (src_id = 55, ChEMBL Document IDs CHEMBL4649982-CHEMBL4649998): The EUbOPEN consortium is an Innovative Medicines Initiative (IMI) funded project to enable and unlock biology in the open. The aims of the project are to assemble an open access chemogenomic library comprising about 5,000 well annotated compounds covering roughly 1,000 different proteins, to synthesiz

Identifying relevant compounds in patents

  As you may know, patents can be inherently noisy documents which can make it challenging to extract drug discovery information from them, such as the key targets or compounds being claimed. There are many reasons for this, ranging from deliberate obfuscation through to the long and detailed nature of the documents. For example, a typical small molecule patent may contain extensive background information relating to the target biology and disease area, chemical synthesis information, biological assay protocols and pharmacological measurements (which may refer to endogenous substances, existing therapies, reaction intermediates, reagents and reference compounds), in addition to description of the claimed compounds themselves.  The SureChEMBL system extracts this chemical information from patent documents through recognition of chemical names, conversion of images and extraction of attached files, and allows patents to be searched for chemical structures of interest. However, the curren

Julia meets RDKit

Julia is a young programming language that is getting some traction in the scientific community. It is a dynamically typed, memory safe and high performance JIT compiled language that was designed to replace languages such as Matlab, R and Python. We've been keeping an an eye on it for a while but we were missing something... yes, RDKit! Fortunately, Greg very recently added the MinimalLib CFFI interface to the RDKit repertoire. This is nothing else than a C API that makes it very easy to call RDKit from almost any programming language. More information about the MinimalLib is available directly from the source . The existence of this MinimalLib CFFI interface meant that we no longer had an excuse to not give it a go! First, we added a BinaryBuilder recipe for building RDKit's MinimalLib into Julia's Yggdrasil repository (thanks Mosè for reviewing!). The recipe builds and automatically uploads the library to Julia's general package registry. The build currently targe

New Drug Warnings Browser

As mentioned in the announcement post of  ChEMBL 29 , a new Drug Warnings Browser has been created. This is an updated version of the entity browsers in ChEMBL ( Compounds , Targets , Activities , etc). It contains new features that will be tried out with the Drug Warnings and will be applied to the other entities gradually. The new features of the Drug Warnings Browser are described below. More visible buttons to link to other entities This functionality is already available in the old entity browsers, but the button to use it is not easily recognised. In the new version, the buttons are more visible. By using those buttons, users can see the related activities, compounds, drugs, mechanisms of action and drug indications to the drug warnings selected. The page will take users to the corresponding entity browser with the items related to the ones selected, or to all the items in the dataset if the user didn’t select any. Additionally, the process of creating the join query is no