Using the cannabidiol Epidiolex in combination with Diacomit (stiripentol) or Depacon (sodium valproate) — two anti-epileptic treatments — does not seem to raise major safety concerns among patients with seizures caused by conditions such as Lennox-Gastaut syndrome (LGS), a Phase 2 study reported.
A small rise in the blood concentrations of Diacomit were observed with the Epidiolex combination, but no changes of clinical importance were seen with the Depacon combo, the researchers said.
However, individual responses were seen to vary. Thus, the investigators recommended that those who use Epidiolex with Diacomit should be closely monitored for any possible adverse effects.
The study, “A Phase II Randomized Trial to Explore the Potential for Pharmacokinetic Drug-Drug Interactions with Stiripentol or Valproate when Combined with Cannabidiol in Patients with Epilepsy,” was published in the journal CNS Drugs.
Epidiolex, marketed by Greenwich Biosciences, a subsidiary company of GW Pharmaceuticals, is an oral cannabidiol solution derived from cannabis that has strong anti-seizure, anti-psychotic, and anti-anxiety (anxiolytic) properties.
The therapy was found in previous clinical trials to be a safe and effective option for lowering the frequency of seizures in children with Lennox-Gastaut and Dravet syndromes, two drug-resistant forms of epilepsy.
These observations led to the approval of Epidiolex in the U.S. for the treatment of seizures in children with LGS and Dravet, ages 2 and older. The cannabidiol, under the brand name Epidyolex, also was approved in the E.U. as an add-on therapy to clobazam for the same indications.
Children with drug-resistant forms of epilepsy are usually treated with combinations of multiple anti-seizure medications. These include Diacomit, which is sold by Biocodex, and Depacon, marketed by AbbVie. Because of these combinations, clinical studies investigating possible drug-drug interactions between Epidiolex and these medications, as well as potential adverse therapeutic reactions stemming from these interactions, are necessary.
Here, researchers at the University of Gothenburg in Sweden, along with the scientists from GW Research, designed a Phase 2 clinical trial (NCT02607891) to evaluate how Epidiolex affects Depacon or Diacomit, as well as the safety and tolerability of Epidiolex in people using these anti-epileptic medicines.
The trial enrolled 35 patients, ages 16-55, who were receiving a stable dose of Diacomit or Depacon — but no other anti-epileptic medicines — to control their seizures.
The participants were randomly assigned to receive either Epidiolex (20 mg/kg/day), or a placebo, in combination with their original treatment regimen.
Among those who completed the study and were included in the analysis, 14 people in the Depacon arm were given Epidiolex and four a placebo. Meanwhile, 10 participants in the Diacomit arm were given the cannabidiol and two a placebo.
The first dose of Epidiolex, or placebo, was given two days after the participants took their anti-epileptic medicines. A 10-day dose-escalation period was followed by a 14-day maintenance period, after which the patients were invited to enter an open-label extension (OLE) study.
For the individuals who did not participate in the OLE, the cannabidiol dose was reduced over 10 days; they then returned to the clinic for follow-up.
Blood samples were collected from all participants on day one, before receiving Epidiolex, and at day 26, for pharmacological analyses. Safety assessments also were conducted to examine possible treatment-related adverse events.
The results showed that the blood levels of Diacomit were slightly higher (17%) in the presence of Epidiolex, and in concentration measurements over time (30%), compared with Diacomit alone. However, such increases were not seen in all patients in this study arm.
In contrast, blood concentrations of Depacon were slightly lower (13%) in the presence of Epidiolex compared with those taking the anti-epileptic treatment alone. However, there were no apparent differences in the blood levels over time between the two groups. Levels of a Depacon metabolite called 4-ene-VPA also were lower in those receiving the combination with Epidiolex compared with those taking just the anti-epileptic.
The safety profile of Epidiolex was consistent with previous reports. Eight people (57%) in the Diacomit plus Epidiolex group experienced an adverse event, most often mild diarrhea and fatigue. Adverse effects also were more common in those taking both Depacon and Epidiolex (88%) than the anti-epileptic alone (25%), with mild diarrhea accounting for the most reported side effect.
Although most adverse events were only mild in severity, two serious adverse events — rash and hypertransaminasemia (high liver enzymes) — resulted in two participants discontinuing treatment with Epidiolex. One patient in the Depacon/Epidiolex arm withdrew from the trial, as did one in the Diacomit/Epidiolex arm.
“Concomitant cannabidiol led to a small increase in [Diacomit] exposure,” the researchers concluded.
However, they added: “The clinical relevance of the increase in [Diacomit] exposure is unknown; patients receiving cannabidiol and [Diacomit] concomitantly should be monitored for adverse reactions as individual patient responses may vary.”