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(Abst. 1.297), 2018

A Phase 1 Investigation Into the Potential Effects of Cannabidiol on CYP3A4-Mediated Drug-Drug Interactions in Healthy Volunteers
Authors: Gilmour Morrison, GW Research Ltd; Lesley Taylor, GW Research Ltd; Julie Crockett, GW Research Ltd; David Critchley, GW Research Ltd; and Bola Tayo, GW Research Ltd
Content: Rationale: A pharmaceutical formulation of highly purified cannabidiol oral solution (CBD) has been studied for the add-on treatment of rare, treatment-resistant, childhood-onset epilepsies, including Lennox-Gastaut and Dravet syndromes. In vitro metabolism studies have suggested CBD may both inhibit and induce cytochrome P450 (CYP)3A4. Given the interaction potential of CBD with CYP3A4 substrates, which include some commonly used antiepileptic drugs, this phase 1 healthy volunteer trial investigated the effect of steady-state CBD administration on the pharmacokinetics (PK) of the sensitive CYP3A4 probe substrate midazolam. In addition, the safety and tolerability of CBD when co-administered with midazolam were evaluated. Methods: This fixed sequence crossover trial investigated the effect of multiple dose (24 days) administration of CBD on CYP3A4 activity using midazolam as a probe substrate in 16 subjects. All subjects received a single oral dose of placebo (matched to CBD) together with a single oral dose of 2.5 mg midazolam on Day -1. Subjects self-administered escalating doses of CBD with food from Days 1 (250 mg once daily) to 11 (750 mg twice daily [b.i.d.]), followed by 14 days of 750 mg CBD b.i.d. (Days 12–25). On Day 25, subjects received a single oral dose of 2.5 mg midazolam together with the morning CBD dose. Plasma concentrations of midazolam were determined using validated bioanalytical methods. Safety parameters were monitored throughout the trial. Results: Exposure to midazolam was similar when co-administered with either placebo or CBD at steady state. The ratio of geometric least squares (LS) means (90% confidence interval [CI]) comparing midazolam + placebo (Day -1) vs. midazolam + CBD (Day 25) was 0.922 (0.778, 1.09) for AUC0-t, 0.921 (0.776, 1.09) for AUC0-8 and 0.779 (0.667, 0.956) for Cmax (Table 1). Absorption of midazolam was rapid with and without concomitant CBD administration; median tmax was 0.5 hours (range: 0.48-2.00 hours) with placebo vs. 1.0 hour (range: 0.50-3.00 hours) with CBD (Table 1). Midazolam t½ was relatively unaffected by concomitant administration of CBD; the arithmetic mean t½ was 4.99 hours with placebo and 4.53 hours with CBD. CBD was generally well tolerated throughout the trial; the safety results were consistent with the current safety profile of CBD. All reported treatment-emergent adverse events (AEs) were of mild or moderate severity; most were mild (Table 2). Two moderate AEs, rash erythematous and hepatic enzyme increased, resulted in discontinuation of CBD and subject withdrawal. Conclusions: After multiple administrations of CBD at steady state, there were no notable effects on the PK of the sensitive CYP3A4 substrate midazolam. Thus, it is predicted that CBD is unlikely to have any clinically meaningful effects on exposure to drugs that are extensively metabolized by this isoform. Funding: GW Research Ltd
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