CBD leads to a clinically relevant drug interaction with clobazam (strongly increased norclobazam levels), but enables a >50% seizure reduction in 70% of patients.
Summary
n=13 children with treatment-refractory epilepsy under clobazam (CLB) + CBD (IND study): 9 of 13 patients (70%) showed >50% seizure reduction. CLB levels increased by 60±80% (95% CI –2 to 91%) at 4 weeks; N-desmethylclobazam (nCLB) by 500±300% (95% CI +90 to +610%). CLB dose reduced in 10 of 13 patients (77%); adverse effects in 10 of 13 (77%), resolved by CLB dose reduction.
P
PopulationChildren with refractory epilepsy under concurrent clobazam therapy, n=13
I
InterventionCannabidiol (CBD) as adjuvant therapy (expanded access, IND 119876), dose not specified, oral, over at least 8 weeks
O
OutcomeMean increase in nCLB levels of 500 ± 300% (95% CI +90–610%) after 4 weeks; 9/13 patients (70%) showed >50% seizure reduction; adverse effects in 77%, manageable through CLB dose reduction
Confidence in the evidence
Very lowLowModerateHigh
Moderate
The third of four GRADE levels, the effect estimate is probably reliable.
<h4>Objective</h4>Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P450 (CYP) pathway, we predicted a drug-drug interaction, which we evaluate in this article.<h4>Methods</h4>Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demographic information was collected for each subject including age, sex, and etiology of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB, N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored.<h4>Results</h4>We report elevated CLB and nCLB levels in these subjects. The mean (± standard deviation [SD]) increase in CLB levels was 60 ± 80% (95% confidence interval (CI) [-2-91%] at 4 weeks); the mean increase in nCLB levels was 500 ± 300% (95% CI [+90-610%] at 4 weeks). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction.<h4>Significance</h4>Monitoring of CLB and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.