Clobazam
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Mechanism of action
The exact mechanism of action for clobazam, a 1,5-benzodiazepine, is not fully understood but is thought to involve the potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABA<sub>A</sub> receptor. Specifically, clobazam binds to the interface of the α<sub>2</sub> and γ<sub>2</sub>-subunit of the GABA<sub>A</sub> receptor. It has a great affinity for the α<sub>2</sub> subunit than the α<sub>1</sub> subunit compared to other 1,4‐benzodiazepines.Binding of clobazam to the GABA<sub>A</sub> receptor causes chloride channels to open, resulting in an influx of chloride and thus hyperpolarization of neurons.
Pharmacodynamics
Clobazam belongs to the benzodiazepine class of drugs. Clobazam acts on the GABA<sub>A</sub> 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.
Pharmacokinetics
Half-life
The estimated mean elimination half-lives (t½) of clobazam and N-desmethylclobazam were 36-42 hours and 71-82 hours, respectively.
The mean elimination half-life of clobazam is approximately 36-42 hours and the mean elimination half-life of N-desmethylclobazam is approximately 71-82 hours.
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.
N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine. Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.
Clobazam is lipophilic and distributes rapidly throughout the body. The apparent volume of distribution at steady state was approximately 100 L.
After a 20 to 40 mg/day administration of clobazam, the oral clearance is calculated to be 1.9 to 2.3 L/h.
/MILK/ Onfi is excreted in human milk.
/MILK/ After oral administration of (14)C-clobazam (NH-15,7- chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4-(3H,5H)-dione) (4 mg/kg) to pregnant and lactating rats, the placental transfer and the secretion of radioactivity into milk were studied. Whole body autoradiograms of pregnant rats showed that radioactivity was distributed to the whole body of the fetus. Concentrations of radioactivity in fetal brain and blood were lower than the maternal plasma and placental levels, and decreased rapidly. The extent of transfer of radioactivity into the fetus reached maximum at 30 min after administration, amounting to 0.10% of the radioactivity administered per fetus. The composition of clobazam and its metabolites in plasma of pregnant rats at 30 min after oral administration was similar to that of non-pregnant rats. Concentration of radioactivity in the milk was 1.4 times higher than that in the blood, reached maximum 30 min after administration, then declined rapidly. The radioactivity transferred to the suckling via milk reached a maximum of 0.023% of the dose up to 8 hr after administration. Excretion of radioactivity from the suckling was slow. The composition of clobazam and its metabolites in aggregated milk in the suckling stomach was similar to that of female rat plasma.
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.
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.
Clobazam is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug. The major metabolic pathway of clobazam involves N-demethylation, 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 parent compound range from 1/5 to equal potency. N-desmethylclobazam is extensively metabolized, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise approximately 94% of the total drug-related components in urine. Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.
A four-year-old male with symptomatic generalized epilepsy presented with ataxia, eye rolling, and episodes of back arching which were of non-epileptic origin following the introduction of clobazam at 0.75 mg/kg/day. Concurrent antiepileptic medication was lamotrigine at 13 mg/kg/day. Clobazam plasma levels were within the normal range, while N-desmethylclobazam (DCLB) concentrations were between five and seven times above the upper limit of the normal range. The plasma elimination half-life for DCLB was prolonged, suggesting a genetic variability in DCLB metabolism leading to toxicity. Reduction in the dose of clobazam to 0.3 mg/kg/day was associated with resolution of the non-epileptic neurological symptoms, reduction in DCLB plasma levels, and maintenance of seizure control.
Clobazam has known human metabolites that include 4-Hydroxyclobazam and N-desmethylclobazam.
Clobazam is extensively metabolized in the liver via N-demethylation and hydroxylation. Clobazam has two major metabolites: N-desmethylclobazam (norclobazam) and 4'-hydroxyclobazam, the former of which is active. Norclobazam is one-fourth the potency of clobazam. The main enzyme that facilitates the process of N-demethylation is CYP3A4, and to a lesser extent by CYP2C19 and CYP2B6. Norclobazam itself is also metabolized via hydroxylation, primarily by CYP2C19. The formation of 4'-hydroxyclobazam is facilitated by CYP2C18 and CYP2C19. A factor in determining extent of metabolism is the genetic profile of the individual patient as CYP2C19 is a polymorphic enzyme.
Route of Elimination: Clobazam is eliminated via the urine (~94%) as metabolites.
Half Life: The mean elimination half life of an oral dose of clobazam 40 mg is 32 hours. It's main metabolite, norclobazam, as a half life of 57 hours. The half life in adult patients with epilepsy are higher than those that are healthy.
Protein binding
The in vitro plasma protein binding of clobazam and N-desmethylclobazam is approximately 80-90% and 70%, respectively.
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