title: Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, U.S.A.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Geffrey
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, U.S.A.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Pollack
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, U.S.A.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Bruno
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, U.S.A.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Thiele
mesh_terms: D000293:Adolescent; D001569:Benzodiazepines / Q000378:metabolism / Q000627:therapeutic use*; D002185:Cannabidiol / Q000378:metabolism / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D000078306:Clobazam; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D055815:Young Adult
chemical_list: D001569:Benzodiazepines; D002185:Cannabidiol; D000078306:Clobazam; D003577:Cytochrome P-450 Enzyme System; C024581:N-desmethylclobazam
keywords: Antiepileptic drugs; Cannabis; Cytochrome P450 pathway; Norclobazam; Treatment-resistant epilepsy