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Thursday, 27 October 2011

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.

1 comment:

Vladimir Chupakhin said...

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