Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs

Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials. It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs). CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites. One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD. There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2-propyl-4-pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA. The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.     

EEG-Brain mapping,psychometric and psychophysiological studies on central effects of kavain - a kava plant derivative

In a double-blind, placebo-controlled study the encephalotropic and psychotropic effects of kavain-a synthetic kava plant derivative as compared with clobazam were investigated, utilizing EEG brain mapping, psychometric and psychopysiological analyses. 15 normal volunteers received randomized in weekly intervals single oral doses of placebo, 200 mg, 400 mg and 600 mg kavain as well as 30 mg clobazam as reference compound. EEG recordings, psychometric tests, evaluations of pulse, blood pressure and side effects were carried out at the hours 0, 1, 2, 4, 6 and 8. Brain maps of drug induced pharmaco-EEG changes (pharmaco-EEG maps) demonstrated that kavain exerted a significant action on the human brain function as compared with placebo characterized by a dose-dependent increase of delta, theta and alpha 1 activity while alpha 2, beta activity and the centroid of the total activity decreased. These findings are indicative of a sedative effect which was, however, in type quite different from that of the 1·5 benzodiazepine. The latter produced a decrease of delta, theta, alpha 1 and alpha 2 and an increase of beta activity while the total centroid was accelerated. Interestingly, 200 mg kavain induced with a decrease of delta and beta activity and an increase of alpha activity and of total power also vigilance promoting effects. Psychometric investigations demonstrated also clear differences between the two compounds at the behavioural level. Kavain improved the noopsyche as compared with placebo in all 3 doses as there was a significant improvement in intellectual performance (Pauli test), attention, concentration, reaction time and motor speed (rigidity test), while opposite findings were observed after 30 mg clobazam. In regard to thymopsychic variables such as drive, wakefulness, affectivity, mood, well-being, 200 mg kavain produced an improvement as compared with placebo while 600 mg kavain produced sedation as did 30 mg clobazam. Psychophysiological evaluations resulted in only minimal findings. Time efficacy calculations demonstrated after kavain a pharmacodynamic peak in the 1st to the 2nd hour then a drop and a second peak in the 8th hour while clobazam produced maximal central effects in the 1st hour which declined thereafter to show a second peak in the 6th hour. Topographically, most encephalotropic effects were found after kavain in the frontal, after clobazam in the central and parietal areas. Evaluations of pulse, blood pressure and side effect demonstrated good tolerability of both compounds with 30 mg clobazam producing more sedation than kavain.     

Effects of clobazam and clonazepam on saccadic eye movements and other parameters of psychomotor performance

Summary The effects of two benzodiazepine anti-convulsants clobazam (20 mg) and clonazepam (2 mg) in a variety of psychomotor performance tests were compared in a placebo controlled double-blind acute oral dose study in ten healthy volunteers. Assessments included critical flicker fusion (CFF) threshold, the Sternberg memory scanning and choice reaction time (CRT), peak saccadic velocity (PSV) and visual analogue scales, all previously shown to be sensitive to the effects of benzodiazepines.Clobazam did not significantly impair saccadic eye movements, CFF threshold, Sternberg memory scanning and CRT compared to placebo. Clonazepam significantly lowered PSV, reduced the CFF threshold, slowed the Sternberg CRT and decreased an alertness factor in the visual analogue scales compared to placebo. Clonazepam significantly increased memory scanning time compared to clobazam. Clobazam was remarkably free of cognitive and psychomotor side-effects.     

Study of effects of clobazam and lorazepam on memory and cognitive functions in healthy subjects

This was a double-blind, placebo-controlled crossover study in 15 healthy female volunteers. It consisted of five sessions, separated by 1 week wash-out between sessions. The purpose of the trial was to study the potential amnesic and sedative activity of clobazam and lorazepam, and the potential antagonism between these effects under the joint influence of a high noise level and intense intermittent light stimulation (ILS), aimed at increasing the level of alertness. The study drugs were administered as a single daily oral dose. The amnesic and sedative effects were evaluated by objective measurements (digit span, Buschke selective reminding test, critical flicker fusion, reaction time, tapping, mental arithmetic test) and subjective measurements (visual analogue scale and adverse effect questionnaire) before each administration, then 1 h, 2 h, 2·5 h, 3 h, 4 h and 7 h post-dosing. An analysis of variance according to a balanced Latin square design was performed. Clobazam, at a dosage of 10 mg, was devoided of sedative and amnesic effects; at a dosage of 30 mg it induced only moderate memory disturbances. In contrast, lorazepam, administered at doses of 1 and 3 mg, produced marked and dose-dependent disturbances of memory, alertness and cognitive functions. The use of visual and sound stimuli, designed to increase the level of alertness, did not counteract the sedative effects induced by lorazepam.     

The long-term effect of clobazam as adjunctive therapy in epilepsy

Thirty drug-resistant epilepsy patients were given 20-30 mg of clobazam in addition to their other anticonvulsants and followed up for 2-3 years in an open-ended study. Fit frequency was markedly reduced in 43% of patients, few side effects occurred and psychological parameters including the Crown-Crisp questionnaire, showed improvement. It therefore seems that clobazam is a useful additional drug added to conventional anticonvulsant regimes.     

Clobazam and diazepam: The differential effects on psychomotor performance and subjective feelings in normal volunteers with high neuroticism level

The purpose of this study was to investigate the possible differences between diazepam and clobazam with regard to their effects on psychomotor performance and subjective feeling in normal volunteers with high neuroticism levels. The study was designed as a double-blind, crossover, single-dose comparison of clobazam, diazepam, and placebo. Using the Maudsley Personality Inventory (MPI), 12 healthy male volunteers exhibiting high neuroticism scores were selected. Clobazam 10 mg, diazepam 5 mg, and placebo were administered orally. Measurements of psychomotor performance and subjective ratings of mood states were performed before and 1.5 and 6 hr after administration. Prior to the experiment the subjects were trained with the performance tests to minimize interference of learning effects with drug effects. Between the three treatments there were 1-wk intervals. Both clobazam and diazepam significantly lowered choice-reaction task performance as compared to placebo. Only clobazam lowered mirror-drawing task performance significantly differently from placebo. Significant changes in subjectively rated mood states were also seen after clobazam only. These mood changes appeared to indicate some disinhibitory or stimulant effects. The demonstrated differences between the effects of both anxiolytics are discussed in the context of experimental design characteristics and the subjects' high level of neuroticism. Some of the observed effects may be due to an interaction of drug effects with neurotic tendencies rather than to generalized drug effects per se.     

Single and multiple dose kinetics of clobazam,and clinical effects during multiple dosage

Summary Sixteen healthy volunteers, aged 19 to 62 years, took a single 20-mg oral dose of clobazam and the serum concentrations of clobazam and desmethylclobazam were measured for the following 7 days. The mean kinetic variables for clobazam were: volume of distribution 1.31/kg, elimination half-life 24 h, total clearance 0.47 ml/min/kg. 13 of the volunteers then took clobazam 5 mg twice daily for 22 consecutive days. Serum concentrations were measured during and after this period. Both clobazam and desmethylclobazam showed slow and extensive accumulation, their steady-state kinetics being entirely consistent with those observed after single doses. Elimination of both compounds after termination of treatment was equally slow. Clinical self-rating of morning sedation indicated a significant increase over baseline in subjective perception of sedation during the treatment period, and this effect persisted into the washout period. However, sedation did not increase in parallel with accumulating levels of clobazam and desmethylclobazam, probably due to functional adaptation or tolerance.This work was part of the doctoral thesis of Dr. M. Lüttkenhorst, University of Bonn, 1982