Clobazam pathway, pharmacokinetics

Inspired by a patient with levels clobazam 397 desmethylclobazam < 200.

Courtesy of a colleague.

Huddart R, Leeder JS, Altman RB, Klein TE. PharmGKB summary: clobazam pathway, pharmacokinetics. Pharmacogenet Genomics. 2018 Apr;28(4):110-115. doi: 10.1097/FPC.0000000000000327. PMID: 29517622; PMCID: PMC5914180.

Background

Clobazam is an antiepileptic drug (AED) which has been approved by the FDA for use in the treatment of Lennox-Gastaut Syndrome in patients 2 years and older. Outside of the U.S., clobazam is also used as an adjunctive therapy for refractory epilepsy and to treat other epileptic syndromes and anxiety. It is a 1,5-benzodiazepine, distinguished by the presence of a nitrogen atom at positions 1 and 5 of the benzodiazepine ring rather than at positions 1 and 4 as seen in the 1,4-benzodiazepines (e.g. diazepam) . At the time of writing, clobazam is the only 1,5-benzodiazepine in clinical use. The main metabolite of clobazam, norclobazam, is also clinically active and exerts an antiepileptic effect.

Epileptic seizures are thought to be caused by excessive excitatory action potentials in neurons.  Clobazam and norclobazam exert their effects by binding to postsynaptic GABAA receptors in the brain, ultimately causing hyperpolarization of the neuron to create an inhibitory signal. This hyperpolarization increases the action potential threshold, thereby reducing the frequency of action potentials and the likelihood of seizures. This is discussed in greater detail in the Pharmacodynamics section below.

Clobazam is generally considered to cause fewer side-effects and cutaneous reactions, such as Stevens-Johnson Syndrome (SJS) or toxic epidermal necrolysis (TEN), at a lower rate than other AEDs, such as the 1,4-benzodiazepine carbamazepine. Cases of SJS/TEN have been reported in patients taking clobazam, often in combination with the 1,4-benzodiazepine lamotrigine and valproic acid. As lamotrigine is associated with a high risk of SJS/TEN and clobazam and lamotrigine are not thought to interact with each other, it seems likely that lamotrigine is inducing SJS/TEN in these cases.

The FDA has identified 21 cases of SJS/TEN from both the US and abroad, many of these in children. As a result, they have released a warning about the potential for clobazam to cause SJS/TEN at https://www.fda.gov/drugs/drugsafety/ucm377204.htm. However, it should be noted that, in 19 of these cases, the patient was taking one or more concomitant drugs which are also associated with SJS/TEN , many of which are themselves considered to be high risk for SJS/TEN. Indeed, a recent case-control study of 480 cases of SJS/TEN found no causal association between clobazam and SJS/TEN.