Chemical formula: C₁₆H₁₃ClN₂O₂ Molecular mass: 300.74 g/mol PubChem compound: 2789
Clobazam is a 1,5-benzodiazepine and the pharmacodynamic activity is qualitatively similar to that of other compounds of this class:
These effects are related to a specific agonist action upon a central part of the receptor complex “Gaba-Omega macromolecular receptors”. Also known as BZ1 and BZ2 and modulating the opening of the chloride channel.
In single doses up to 20mg or in divided doses up to 30mg, clobazam does not affect psychomotor function, skilled performance, memory or higher mental functions.
After oral administration, clobazam is rapidly and extensively absorbed
Time to peak plasma concentrations (Tmax) is achieved from 0.5–4.0 hrs. The administration of clobazam tablets with food or crushed in applesauce slows the rate of absorption by approximately 1 hour, but it does not affect the overall extent of absorption. Clobazam can be given without regard to meals. Concomitant intake of alcohol can increase the bioavailability of clobazam by 50%.
After a single dose of 20 mg clobazam, marked inter-individual variability in maximum plasma concentrations (222 to 709 ng/ml) was observed after 0.25 to 4 hours. Clobazam is lipophilic and distributes rapidly throughout the body. Based on a population pharmacokinetic analysis, the apparent volume of distribution at steady-state was approximately 102 L, and is concentration independent over the therapeutic range. Approximately 80-90% of clobazam is bound to plasma protein.
Clobazam accumulates approximately 2-3 fold to steady-state while the active metabolite N-desmethylclobazam (N-CLB) accumulates approximately 20-fold following clobazam twice daily administration. Steady state concentrations are reached within approximately 2 weeks.
Clobazam is rapidly and extensively metabolized in the liver. Clobazam metabolism occurs primarily by hepatic demethylation to N-desmethylclobazam (N-CLB), mediated by CYP3A4 and to a lesser extent by CYP2C19. N-CLB is an active metabolite and the main circulating metabolite found in human plasma.
N-CLB undergoes further biotransformation in the liver to form 4-hydroxy-N-desmethylclobazam, primarily mediated by CYP2C19.
CYP2C19 poor metabolizers exhibit a 5-fold higher plasma concentration of N-CLB compared to extensive metabolizers.
Clobazam is a weak CYP2D6 inhibitor. Co-administration with dextromethorphan led to increases of 90% in AUC and 59% in Cmax values for dextromethorphan.
Based on a population pharmacokinetic analysis, plasma elimination half-lives of clobazam and N-CLB were estimated to be 36 hours and 79 hours respectively.
Clobazam is cleared mainly by hepatic metabolism with subsequent renal elimination. In a mass balance study, approximately 80% of the administered dose was recovered in urine and about 11% in the faeces. Less than 1% of unchanged clobazam and less than 10% of unchanged N-CLB are excreted through the kidneys.
A study in which clobazam (150, 450, or 750 mg/kg/day) was orally administered to pregnant rats throughout the period of organogenesis, embryo-fetal mortality and incidences of fetal skeletal variations were increased at all doses. The low effect dose for developmental toxicity in rats (150 mg/kg/day) was associated with plasma exposures (AUC) for clobazam and desmethylclobazam less than those in humans at the maximum recommended human dose of 60 mg/day.
Oral administration of clobazam (10, 30, or 75 mg/kg/day) to pregnant rabbits throughout the period of organogenesis resulted in decreased fetal body weights, and increased incidences of fetal malformations (visceral and skeletal) at the mid and high doses, and an increase in embryo-fetal mortality at the high dose. Incidences of fetal variations were increased at all doses. The highest dose tested was associated with severe maternal toxicity (mortality). The low effect dose for embryo-fetal toxicity in rabbits (10 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam less than those in humans at the maximum recommended human dose of 60 mg/day.
Additionally, oral administration of clobazam (50, 350, or 750 mg/kg/day) to rats throughout pregnancy and lactation resulted in increased embryo-fetal mortality at the high dose, decreased pup survival at the mid and high doses and alterations in offspring behaviour (locomotor activity) at all doses.
The low effect dose for pre- and postnatal development in rats (50 mg/kg/day) was associated with plasma exposures for clobazam and N-desmethylclobazam less than those in humans at the maximum recommended human dose of 60 mg/day.
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