CLOBAZAM

Absorption

The peak plasma levels (Cmax) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10-80 mg following single- or multiple-dose administration of ONFI. Based on a population pharmacokinetic analysis, the pharmacokinetics of clobazam are linear from 5-160 mg/day.
Clobazam is rapidly and extensively absorbed following oral administration. The time to peak concentrations (Tmax) of clobazam tablets under fasted conditions ranged from 0.5 to 4 hours after single- or multiple-dose administrations. The relative bioavailability of clobazam tablets compared to an oral solution is approximately 100%. After single-dose administration of the oral suspension under fasted conditions, the Tmax ranged from 0.5 to 2 hours. Based on exposure (Cmax and AUC) of clobazam, clobazam tablets and suspension were shown to have similar bioavailability under fasted conditions. The administration of clobazam tablets with food or when crushed in applesauce does not affect absorption. Although not studied, the oral bioavailability of the oral suspension is unlikely to be affected under fed conditions.

Chemical properties

N/AWhite Solid

Originator

Urbanyl,Diamant,France,1975

The Uses of CLOBAZAM

Benzodiazepine psychotherapeutic agent. Clobazam (CLB) has proven efficacy against multiple seizure types. Controlled substance (depressant).

Background

Clobazam belongs to the 1,5-benzodiazepine class of drugs and is marketed under different names, Onfi, Frisium, Urbanyl, and others.. Clobazam was first synthesized in 1966 and first published in 1969, following the incidental synthesis and discovery of the first benzodiazepine chlordiazepoxide in the 1950s. Unlike older 1,4-benzodiazepines, clobazam has a better side-effects profile, particularly less sedative and amnesic effects. This is likely because of clobazam's higher affinity to the α2 subunit of the GABAA receptor, which mediates anxiolytic effects, than the α1 subunit, which mediates sedative effect. Additionally, clobazam is believed to be a partial agonist to the GABAA receptor rather than non-selective full receptor agonists like 1,4-benzodiazepines, thus potentially explaining the decreased incidence of sedative effects.
Clobazam has been marketed as an anxiolytic since 1975 and an anticonvulsant since 1984. In October 21, 2011, the FDA approved clobazam as an adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in adults and children aged two years and older. In 2005, clobazam also received approval from Health Canada as an add-on therapy for generalized tonic-clonic, myoclonic, and focal impaired awareness seizures.

Indications

Clobazam is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older.

Definition

ChEBI: 7-Chloro-1H-1,5-benzodiazepine-2,4(3H,5H)-dione in which the hydrogen attached to the nitrogen at position 1 is substituted by a methyl group, whilst that attached to the other nitrogen is substitute by a phenyl group. It is used for the short-term management of acute anxiety and as an adjunct in the treatment of epilepsy in association with other antiepileptics.

Manufacturing Process

1.65 g of N-phenyl-N-(2-amino-5-chlorophenyl)-malonic acid ethyl ester amide of MP 108° to 109°C are added to a sodium ethoxide solution, prepared from 20 ml of absolute alcohol and 150 mg of sodium. The solution is allowed to rest for 5 hours at room temperature. Then 1 ml of methyl iodide is added and the reaction mixture is refluxed for 7 hours. After evaporation of the solution in vacuo it is mixed with water and the solution is shaken with
methylene chloride. The methylene chloride phase is dried and evaporated. By treatment of the residue with ethyl acetate/charcoal are isolated 500 mg of 7- chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione of MP 180° to 182°C. The yield amounts to 34% of theory

brand name

Urbanyl (Hoechst- Roussel).

Therapeutic Function

Tranquilizer

Pharmacokinetics

Clobazam belongs to the benzodiazepine class of drugs. Clobazam acts on the GABAA receptor to increase GABAnergic transmission, particularly chloride conductance in neurons. This causes neuronal hyperpolarization, resulting in an increase in the action potential threshold and reducing neuron firing frequency. Consequently, the general neuronal activity of the central nervous system is depressed; therefore, clobazam can be used to treat diseases caused by excessive excitatory action potentials.
The effect of clobazam 20 mg and 80 mg administered twice daily on QTc interval was evaluated in a randomized, evaluator-blinded, placebo-, and active-controlled (moxifloxacin 400 mg) parallel thorough QT study in 280 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on the Fridericia correction method was below 10 ms, the threshold for regulatory concern. Thus, at a dose two times the maximum recommended dose, clobazam did not prolong the QTc interval to any clinically relevant extent.

Clinical Use

Benzodiazepine:
Anticonvulsant

Anxiolytic

Safety Profile

Poison by ingestion and intraperitoneal routes. Moderately toxic by subcutaneous route. Human systemic effects by ingestion: wakefulness, withdrawal, nausea and vomiting. An experimental teratogen. Other experimental reproductive effects. A tranquhzer. When heated to decomposition it emits very toxic fumes of NOx and Cl-. See also DIAZEPAM.

Drug interactions

Potentially hazardous interactions with other drugs
Antibacterials: metabolism possibly increased by rifampicin.
Antipsychotics: increased sedative effects; serious adverse events reported with clozapine and benzodiazepines.
Antivirals: concentration possibly increased by ritonavir.
Disulfiram: metabolism of clobazam inhibited; increased sedative effects.
Sodium oxybate: enhanced effects of sodium oxybate - avoid.

Metabolism

Clobazam is extensively metabolized in the liver via N-demethylation and hydroxylation to form two major metabolites, N-desmethylclobazam (norclobazam) and 4'-hydroxyclobazam, respectively, with approximately 2% of the dose recovered in urine and 1% in feces as an unchanged drug. The N-demethylation reaction is catalyzed primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3-5 times higher than those of the parent compound. Based on animal and in vitro receptor binding data, estimates of the relative potency of N-desmethylclobazam compared to the parent compound range from 1/5 to equal potency. N-desmethylclobazam is extensively hydroxylated, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine.. The formation of 4'-hydroxyclobazam is facilitated by CYP2C18 and CYP2C19.
The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N-desmethylclobazam. In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers.

Metabolism

Clobazam is metabolised in the liver by demethylation and hydroxylation; the cytochrome P450 isoenzyme CYP2C19 plays a role in its metabolism. Unlike the 1,4-benzodiazepines such as diazepam, clobazam, a 1,5-benzodiazepine, is hydroxylated at the 4-position rather than the 3-position.
Clobazam is excreted unchanged and as its main active metabolite, N-desmethylclobazam, mainly in the urine.