Brivaracetam is an antiepileptic that is partially metabolized by the cytochrome p450 liver enzyme CYP2C19 to an inactive metabolite.

Clobazam is an antiepileptic that is metabolized by the liver to an inactive metabolite. Clobazam is metabolized to norclobazam, an active metabolite, primarily by the cytochrome p450 liver enzyme CYP3A4. Norclobazam is then primarily metabolized by CYP2C19 to an inactive metabolite. Of note, norclobazam (active metabolite) has a longer half-life (71-82 hours) than clobazam (36-42 hours).  

Across populations, CYP2C19 protein alleles can have different genetic variants that impact its ability to metabolize brivaracetam and clobazam. The different alleles of CYP2C19 can produce five different metabolism phenotypes: ultrarapid, rapid, normal, intermediate and poor metabolism. The poor metabolism phenotype has been shown to decrease brivaracetam and norclobazam metabolism, leading to higher drug levels and an increased risk of side effects (e.g. sedation for bricaracetam).  

Patients who are CYP2C19 poor metabolizers have reduced metabolism of brivaracetam leading to higher drug levels. This may increase the risk of side effects and toxicity (e.g. sedation) and lower doses may be needed. The FDA has provided dosing recommendations for CYP2C19 poor metabolizers being prescribed brivaracetam. Please see the table below for these recommendations.  

Patients who are CYP2C19 poor metabolizers have reduced metabolism of norclobazam leading to higher drug levels. This may increase the risk of side effects and toxicity (e.g. sedation) and lower doses may be needed. The FDA has provided dosing recommendations for CYP2C19 poor metabolizers being prescribed clobazam. Please see the table below for these recommendations.

At UCHealth the use of pharmacogenetics when prescribing some antiepileptic drugs will occur in patients who meet the following conditions:

1) Provided a blood or saliva sample to the CCPM biobank, consented for the return of their results, and this sample has undergone genotyping OR the patient is being seen in a clinic which is currently using pharmacogenetic testing as part of standard care (e.g., the UCHealth GI Oncology Clinic). 
2) Are prescribed brivaracetam or clobazam.

For patients enrolled in the biobank, this process takes a minimum of 4-6 weeks but may take several years. Therefore, results will not be available at initial presentation if a patient has not previously enrolled in the biobank.

If you are a provider AND your patient is a CYP2C19 poor metabolizer, an inline medication warning will appear if you attempt to prescribe or refill brivaracetam or clobazamin UCHealth's EHR.  If the inline medication warning is visible, links to resources will be listed for your reference.  There is patient education text available for UCHealth providers to use in discharge paperwork or the after visit summary (AVS).