DDIs between CBD and commonly used antiepileptic drugs (AEDs) is of clinical interest since it is anticipated that CBD will be used concomitantly with other AEDs.

To summarise current understanding of DDIs when CBD is coadministered with CLB, VPA, STP or CYP3A4 substrate.

Effects of multiple-dose CBD on steady-state pharmacokinetics (PK) of CLB, N-desmethyl clobazam (N-CLB), VPA, 4-ene-VPA, and STP, and multiple-dose CLB, VPA, and STP on steady-state PK of CBD and metabolites were evaluated in HVTs. Effects of multiple-dose CBD on steady-state PK of CLB, N-CLB, VPA, and 4-ene-VPA were evaluated in patients with epilepsy. The effect of CBD on CYP3A4 activity was evaluated in HVTs using MDZ as a probe. In all studies, a plant-derived pharmaceutical formulation of highly purified CBD in oral solution (Epidiolex^®; 100 mg/mL) was uptitrated over 10 days to 750 mg twice daily in HVTs (20 mg/kg/day for a 75 kg subject) or 20 mg/kg/day in patients.

Concomitant CBD had no relevant effect on CLB exposure but increased exposure to its active metabolite, N-CLB, in HVTs (3.4 fold) and patients (2.6 fold). Conversely, concomitant CLB increased CBD (by 30%) and its active metabolite, 7-OH-CBD (by 47%). Concomitant CBD had no effect on VPA, or 4-ene-VPA, and slightly increased exposure to STP (by 55%). Concomitant VPA or STP did not alter CBD or its metabolites. CBD had no effect on MDZ clearance. CBD demonstrated a safety profile consistent with previous randomised placebo-controlled trials.

Combination of CBD with CLB resulted in a bidirectional DDI that increased levels of active metabolites of both compounds. There was no evidence of DDI between CBD and VPA, or any effect of CBD on CYP3A4 activity (MDZ). The slight increase of exposure to STP when coadministered with CBD is not expected to result in a clinically important DDI.