Abstracts

Rationale: Cannabidiol oral solution (CBD-OS) is being developed for the adjunctive treatment of rare, childhood-onset epilepsies, including Lennox-Gastaut syndrome and Dravet syndrome. Clobazam (CLB) is a common therapy in these indications so it is important to consider possible drug-drug interactions (DDIs). CBD is metabolized predominantly by cytochrome P450 (CYP) 2C19 to form an active metabolite 7-OH-CBD, which undergoes further oxidative biotransformation to form inactive 7-COOH-CBD. Other CYP enzymes (CYP3A4, CYP1A2, CYP2C9, and CYP2D6) potentially metabolize CBD. CBD can also be directly conjugated by UDP-glucuronosyltransferases (UGTs). CBD inhibits CYP3A4 and CYP2C19. CLB is a CYP3A4 substrate (to a lesser extent CYP2C19), its active metabolite N-desmethylclobazam (N-CLB) is a sensitive CYP2C19 substrate, and both are CYP3A4 inducers. CLB inhibits CYP2D6 probe substrates in vivo and N-CLB is a weak UGT inhibitor. These data suggest there is potential for a bidirectional DDI.As part of a phase 1 healthy volunteer trial, a primary objective, and focus here, was to investigate the impact of CBD-OS on the steady-state pharmacokinetics of CLB and N-CLB and the reciprocal effect of CLB on CBD and its major metabolites. The secondary objective was to evaluate the safety and tolerability of CBD-OS when coadministered with CLB. Additional objectives were to investigate DDIs and safety with other antiepileptic drugs. Methods: This was part of an open-label, fixed sequence, DDI trial and assessed the effect of multiple dose (7-14 days) administration of CBD-OS on steady-state CLB and N-CLB (12 subjects) and of multiple dose (21 days) CLB administration on steady-state CBD and its metabolites (15 subjects). In both arms, dosage regimens were 750 mg CBD-OS twice daily (b.i.d.) and 5 mg CLB b.i.d. The trial was not powered to identify statistically significant differences in exposure when drugs were given alone versus concomitantly.Plasma concentrations of all analytes were determined using validated bioanalytical methods. Safety parameters were monitored throughout the trial. Results: N-CLB exposure (Cmax and AUCtau) increased (3.4-fold) following up to 14 days of concomitant administration of CBD-OS with CLB (Table 1). CLB exposure increased to a much lesser extent (1.2-fold).Twenty-one days of concomitant administration of 5 mg b.i.d. CLB with 750 mg b.i.d. CBD resulted in an increase (Cmax: 1.7-fold; AUCtau: 1.5-fold) in exposure to 7-OH-CBD in all subjects; there was a trend to an increase in 7-COOH-CBD and CBD (Table 1).In both arms, there was no difference in the total number of subjects reporting treatment-emergent adverse events whether taking victim drug alone or victim and perpetrator drugs in combination (Table 2). Conclusions: Combination of CBD with CLB results in a bidirectional DDI of major metabolites of both compounds. The N-CLB increase by CBD-OS is likely mediated by CYP2C19 inhibition. By contrast, the DDI with 7-OH-CBD, 7-COOH-CBD or CBD may be mediated through CYP (CYP2D6) and/or UGT inhibition by CLB and N-CLB. Funding: Funded by GW Research Ltd