The GW Pharmaceuticals cannabidiol formulation, marketed as Epidiolex, did not show any evidence of clinically relevant drug-drug interactions when co-administered in patients with epilepsy.
Elinor Ben-Menachem, MD, PhD
Data from a randomized, double-blind, placebo-controlled phase 2 trial of cannabidiol (CBD; Epidiolex, GW Pharmaceuticals) in adult patients with epilepsy suggests that there are no likely clinically relevant drug-drug interactions between the treatment and stiripentol (Diacomit, Biocodex).1
The results showed the maximum plasma concentration (Cmax
) at the beginning of treatment was similar to that observed after dosing with CBD, with Day 1 Cmax
being approximately 4500 ng/mL compared to a Day 26 Cmax
of approximately 4900 ng/mL. Time to Cmax
was slightly longer with CBD (~4 hours) than without (~1.5 hours). The data were presented at the 33rd International Epilepsy Congress
, June 22 to 26, 2019 in Bangkok, Thailand,
“Following coadministration of stiripentol and GW Pharmaceuticals’ formulation of highly purified cannabidiol, there was a small increase in systemic exposure to [stiripentol],” the investigators, led by Elinor Ben-Menachem, MD, PhD, professor, neurology, University of Gothenburg, wrote. Importantly, they noted that “this trial was conducted with GW Pharmaceuticals’ formulation of CBD and results cannot be extrapolated to other CBD-containing products.”
Ben-Meachem and colleagues reported the geometric mean and individual patient values of stiripentol doses-normalized pharmacokinetic parameters, with a Cmax
treatment ratio of 1.171 (90% CI, 1.028 to 1.333). Area under the plasma concentration-time curve over a dosing interval (AUCtau
) with and without CBD measurements showed a treatment ratio of 1.298 (90% CI, 1.086 to 1.552).
All told, 12 patients received 10 days of titration followed by 20 mg/kg/day of CBD, given in 2 equal doses for 14 days, and 2 controls received placebo with pharmacokinetic parameters assessed on the first day of titration and at Day 26 after a 2-week maintenance period.
All 14 patients were on a stable dose of stiripentol from the time of titration to Day 26. Only 9 patients had data for both Day 1 and Day 26. Overall, 93% (n = 13) of patients were taking an antiepileptic drug in addition to stiripentol at baseline.
With regard to safety, adverse events (AEs) were reported by 67% (n = 8) of patients who were administered CBD and none receiving placebo, though the majority were deemed mild. The most common AE was diarrhea, occurring in 42% (n = 5) of patients taking CBD. There were 2 moderate AEs reported—an increase in ALT and AST—in 2 patients, though the ALT values for only 1 met the predefined toxicity criteria of ≥2.6x the upper limit of normal but did not exceed the 3x upper limit of normal.
A single severe and serious AE was reported in another patient, a rash, leading to their withdrawal from the trial. It was generalized without mucosal involvement and ultimately resolved after both treatments were discontinued.
Ben-Meacham and colleagues noted that both the CBD steady-state plasma concentrations and pharmacokinetic parameters, as well as the safety data, were consistent with what has been observed in previous trials.
“Many patients with [Dravet syndrome] are treated with multiple antiepileptic drugs, including stiripentol,” they wrote. “A prior phase 1 clinical trial in healthy volunteers showed a 55% increase in exposure to stiripentol, following concomitant CBD treatment, which is unlikely to be clinically relevant.”
Stiripentol, an inhibitor of cytochrome P450 isoenzymes, often has drug-drug interactions with anticonvulsant therapies. It is approved as an add-on therapy for patients taking clobazam (Onfi, Lundbeck), while CBD is approved as a treatment for Lennox-Gastaut and Dravet syndromes.
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1. Ben-Menachem E, Gunning Boudewijn, Cabrera CMA, et al. A phase 2 trial to explore the potential for a pharmacokinetic drug-drug interaction with stiripentol when in combination with cannabidiol (CBD) in patients with epilepsy. Presented at: 2019 International Epilepsy Congress. June 22-26, 2019; Bangkok, Thailand. Poster 338.