Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: GW Research Limited, Sovereign House, Vision Park, Chivers Way, Histon, Cambridge CB24 9BZ, United Kingdom, e-mail: medicalinfo@gwpharm.com
Pharmacotherapeutic group: antiepileptics, other antiepileptics
ATC code: N03AX24
The precise mechanisms by which cannabidiol exerts its anticonvulsant effects in humans are unknown. Cannabidiol does not exert its anticonvulsant effect through interaction with cannabinoid receptors. Cannabidiol reduces neuronal hyper-excitability through modulation of intracellular calcium via G protein-coupled receptor 55 (GPR55) and transient receptor potential vanilloid 1 (TRPV-1) channels, as well as modulation of adenosine-mediated signalling through inhibition of adenosine cellular uptake via the equilibrative nucleoside transporter 1 (ENT-1).
In patients, there is a potential additive anticonvulsant effect from the bi-directional pharmacokinetic interaction between cannabidiol and clobazam, which leads to increases in circulating levels of their respective active metabolites, 7-OH-CBD (approximately 1.5-fold) and N-CLB (approximately 3-fold) (see sections 4.5, 5.1 and 5.2).
The efficacy of cannabidiol for the adjunctive therapy of seizures associated with Lennox-Gastaut syndrome (LGS) was evaluated in two randomised, double-blind, placebo-controlled, parallel-group studies (GWPCARE3 and GWPCARE4). Each study consisted of a 4-week baseline period, a 2-week titration period and a 12-week maintenance period. Mean age of the study population was 15 years and 94% were taking 2 or more concomitant AEDs (cAEDs) during the trial. The most commonly used cAEDs (>25% of patients) in both trials were valproate, clobazam, lamotrigine, levetiracetam, and rufinamide. Approximately 50% of the patients were taking concomitant clobazam. Of the patients that were not taking clobazam, the majority had previously taken and subsequently discontinued clobazam treatment.
The primary endpoint was the percentage change from baseline in drop seizures per 28 days over the treatment period for the cannabidiol group compared to placebo. Drop seizures were defined as atonic, tonic, or tonic-clonic seizures that led or could have led to a fall or injury. Key secondary endpoints were the proportion of patients with at least a 50% reduction in drop seizure frequency, the percentage change from baseline in total seizure frequency, and Subject/Caregiver Global Impression of Change at the last visit.
Subgroup analyses were conducted on multiple factors, including cAEDs. Results of the subgroup analysis of patients treated with clobazam compared to patients treated without clobazam, indicated that there is residual statistical uncertainty regarding the treatment effect of cannabidiol in patients not taking clobazam. In this population, efficacy has not been established.
Table 4 summarises the primary endpoint of percent reduction from baseline in drop seizures, and the key secondary measure of proportion of patients with at least a 50% reduction in drop seizure frequency, as well as results of the subgroup analysis for these outcome measures in patients treated with concomitant clobazam.
Table 4. Primary and ≥50% responder key secondary outcome measures and subgroup analysis in LGS studies:
| Overall | N | Subgroup With Clobazam | N | ||
|---|---|---|---|---|---|
| DROP SEIZURES PER 28 DAYS | |||||
| Percentage Reduction from Baselinea | |||||
| GWPCARE3 | Placebo | 17.2% | 76 | 22.7% | 37 |
| 10 mg/kg/day | 37.2% | 73 | 45.6% | 37 | |
| 20 mg/kg/day | 41.9% | 76 | 64.3% | 36 | |
| GWPCARE4 | Placebo | 21.8% | 85 | 30.7% | 42 |
| 20 mg/kg/day | 43.9% | 86 | 62.4% | 42 | |
| Difference or Percent Reduction Compared with Placebo (95% CI), p-valueb | |||||
| GWPCARE3 | 10 mg/kg/day | 19.2 | 29.6% | ||
| (7.7, 31.2) | (2.4%, 49.2%) | ||||
| p=0.0016 | p=0.0355c | ||||
| 20 mg/kg/day | 21.6 | 53.8% | |||
| (6.7, 34.8) | (35.7%, 66.8%) | ||||
| p=0.0047 | p<0.0001c | ||||
| GWPCARE4 | 20 mg/kg/day | 17.2 | 45.7% | ||
| (4.1, 30.3) | (27.0%, 59.6%) | ||||
| p=0.0135 | p<0.0001c | ||||
| ≥50% REDUCTION IN DROP SEIZURES (RESPONDER ANALYSIS) | |||||
| Percentage of ≥50% Responders, p-valued | |||||
| GWPCARE3 | Placebo | 14.5% | 76 | 21.6% | 37 |
| 10 mg/kg/day | 35.6% | 73 | 40.5% | 37 | |
| p=0.0030 | p=0.0584c | ||||
| 20 mg/kg/day | 39.5% | 76 | 55.6% | 36 | |
| p=0.0006 | p=0.0021c | ||||
| GWPCARE4 | Placebo | 23.5% | 85 | 28.6% | 42 |
| 20 mg/kg/day | 44.2% | 86 | 54.8% | 42 | |
| p=0.0043 | p=0.0140c | ||||
CI=95% confidence interval.
a Data for the overall population are presented as median percent reduction from baseline. Data for the with clobazam subgroup are presented as percent reduction from baseline estimated from a negative binomial regression analysis.
b Overall data are presented as estimated median difference and p-value from a Wilcoxon rank-sum test. Data for the with clobazam subgroup are estimated from a negative binomial regression analysis.
c Nominal p-value.
d The Overall p-value is based on a Cochran-Mantel-Haenszel test; the nominal p-values for the with clobazam subgroup are based on logistic regression analysis.
Cannabidiol was associated with an increase in the percentage of subjects experiencing a greater than or equal to 75% reduction in drop seizure frequency during the treatment period in each trial (11% 10 mg/kg/day cannabidiol, 31% to 36% 20 mg/kg/day cannabidiol, 3% to 7% placebo).
In each trial, patients receiving cannabidiol experienced a greater median percentage reduction in total seizures compared with placebo (53% 10 mg/kg/day, 64% to 66% 20 mg/kg/day, 25% for each placebo group; p=0.0025 for 10 mg/kg/day and p<0.0001 for each 20 mg/kg/day group vs. placebo).
Greater improvements in overall condition, as measured by Global Impression of Change scores at the last visit, were reported by caregivers and patients with both doses of cannabidiol (76% on 10 mg/kg/day, 80% for each group on 20 mg/kg/day, 31% to 46% on placebo; p=0.0005 for 10 mg/kg/day and p<0.0001 and 0.0003 for 20 mg/kg/day vs. placebo).
Compared with placebo, cannabidiol was associated with an increase in the number of drop seizure-free days during the treatment period in each trial, equivalent to 3.3 days per 28 days (10 mg/kg/day) and 5.5 to 7.6 days per 28 days (20 mg/kg/day).
The efficacy of cannabidiol for the adjunctive therapy of seizures associated with Dravet syndrome (DS) was evaluated in two randomised, double-blind, placebo-controlled, parallel-group studies (GWPCARE2 and GWPCARE1). Each study consisted of a 4-week baseline period, a 2-week titration period and a 12-week maintenance period. Mean age of the study population was 9 years and 94% were taking 2 or more cAEDs during the trial. The most commonly used cAEDs (> 25% of patients) in both trials were valproate, clobazam, stiripentol, and levetiracetam. Approximately 65% of the patients were taking concomitant clobazam. Of the patients that were not taking clobazam, the majority had previously taken and subsequently discontinued clobazam treatment.
The primary endpoint was the change in convulsive seizure frequency during the treatment period (Day 1 to the end of the evaluable period) compared to baseline (GWPCARE2), and the percentage change from baseline in convulsive seizures per 28 days over the treatment period (GWPCARE1) for the cannabidiol groups compared to placebo. Convulsive seizures were defined as atonic, tonic, clonic, and tonic-clonic seizures. Key secondary endpoints for GWPCARE2 were the proportion of patients with at least a 50% reduction in convulsive seizure frequency, the change in total seizure frequency, and Caregiver Global Impression of Change at the last visit. The key secondary endpoint for GWPCARE1 was the proportion of patients with at least a 50% reduction in convulsive seizure frequency.
Subgroup analyses were conducted on multiple factors, including cAEDs. Results of the subgroup analysis of patients treated with clobazam compared to patients treated without clobazam, indicated that there is residual statistical uncertainty regarding the treatment effect of cannabidiol in patients not taking clobazam. In this population, efficacy has not been established.
Table 5 summarises the primary endpoint of percent reduction from baseline in convulsive seizures, and the key secondary measure of proportion of patients with at least a 50% reduction in convulsive seizure frequency, as well as results of the subgroup analysis for these outcome measures in patients treated with concomitant clobazam.
Table 5. Primary and ≥50% responder key secondary outcome measures and subgroup analysis in DS studies:
| Overall | N | Subgroup With Clobazam | N | ||
|---|---|---|---|---|---|
| CONVULSIVE SEIZURES PER 28 DAYS | |||||
| Percentage Reduction from Baselinea | |||||
| GWPCARE2 | Placebo | 26.9% | 65 | 37.6% | 41 |
| 10 mg/kg/day | 48.7% | 66 | 60.9% | 45 | |
| 20 mg/kg/day | 45.7% | 67 | 56.8% | 40 | |
| GWPCARE1 | Placebo | 13.3% | 59 | 18.9% | 38 |
| 20 mg/kg/day | 38.9% | 61 | 53.6% | 40 | |
| Difference or Percent Reduction Compared with Placebo (95% CI), p-valueb | |||||
| GWPCARE2 | 10 mg/kg/day | 29.8% | 37.4% | ||
| (8.4%, 46.2%) | (13.9%, 54.5%) | ||||
| p=0.0095 | p=0.0042c | ||||
| 20 mg/kg/day | 25.7% | 30.8% | |||
| (2.9%, 43.2%) | (3.6%, 50.4%) | ||||
| p=0.0299 | p=0.0297c | ||||
| GWPCARE1 | 20 mg/kg/day | 22.8 | 42.8% | ||
| (5.4, 41.1) | (17.4%, 60.4%) | ||||
| p=0.0123 | p=0.0032c | ||||
| ≥50% REDUCTION IN CONVULSIVE SEIZURES (RESPONDER ANALYSIS) | |||||
| Percentage of ≥50% Responders, p-valued | |||||
| GWPCARE2 | Placebo | 26.2% | 65 | 36.6% | 41 |
| 10 mg/kg/day | 43.9% | 66 | 55.6% | 45 | |
| p=0.0332 | p=0.0623c | ||||
| 20 mg/kg/day | 49.3% | 67 | 62.5% | 40 | |
| p=0.0069 | p=0.0130c | ||||
| GWPCARE1 | Placebo | 27.1% | 59 | 23.7% | 38 |
| 20 mg/kg/day | 42.6% | 61 | 47.5% | 40 | |
| p=0.0784 | p=0.0382c | ||||
CI=95% confidence interval.
a For study GWPCARE1, overall data are presented as median percent reduction from baseline. Data for study GWPCARE2 and the with clobazam subgroup are presented as percent reduction from baseline estimated from a negative binomial regression analysis.
b For study GWPCARE1, overall data are presented as estimated median difference and p-value from a Wilcoxon rank-sum test. Data for study GWPCARE2 and the with clobazam subgroup are estimated from a negative binomial regression analysis.
c Nominal p-value.
d The Overall p-value is based on a Cochran-Mantel-Haenszel test; the nominal p-value for the with clobazam subgroup is based on logistic regression analysis.
Cannabidiol was associated with an increase in the percentage of subjects experiencing a greater than or equal to 75% reduction in convulsive seizure frequency during the treatment period in each trial (36% 10 mg/kg/day cannabidiol, 25% for each 20 mg/kg/day cannabidiol group, 10% to 13% placebo).
In each trial, patients receiving cannabidiol experienced a greater percentage reduction in total seizures compared with placebo (66% 10 mg/kg/day, 54% to 58% 20 mg/kg/day, 27% to 41% placebo; p=0.0003 for 10 mg/kg/day and p=0.0341 and 0.0211 for 20 mg/kg/day vs. placebo).
Greater improvements in overall condition, as measured by Global Impression of Change scores at the last visit, were reported by caregivers and patients with both doses of cannabidiol (73% on 10 mg/kg/day, 62% to 77% on 20 mg/kg/day, 30% to 41% on placebo; p=0.0009 for 10 mg/kg/day and p=0.0018 and 0.0136 for 20 mg/kg/day vs. placebo).
Compared with placebo, cannabidiol was associated with an increase in the number of convulsive seizure-free days during the treatment period in each trial, equivalent to 2.7 days per 28 days (10 mg/kg/day) and 1.3 to 2.2 days per 28 days (20 mg/kg/day).
The DS population in studies GWPCARE2 and GWPCARE1 was predominantly paediatric patients, with only 5 adult patients who were 18 years old (1.6%), and therefore limited efficacy and safety data were obtained in the adult DS population.
Given that there was no consistent dose response between 10 mg/kg/day and 20 mg/kg/day in the LGS and DS studies, cannabidiol should be titrated initially to the recommended maintenance dose of 10 mg/kg/day (see Section 4.2). In individual patients titration up to a maximum dose of 20 mg/kg/day may be considered, based on the benefit-risk (see Section 4.2).
Across both randomised LGS studies, 99.5% of patients (N=366) who completed the studies were enrolled into the long-term open-label extension (OLE) study (GWPCARE5). In the subgroup of LGS patients treated with concomitant clobazam for 37 to 48 weeks (N=168), the median percentage reduction from baseline in drop seizure frequency was 71% during Week 1-12 (N=168), which was maintained through to Week 37-48, with a median percentage reduction from baseline in drop seizure frequency of 62%.
Across both randomised DS studies, 97.7% of patients (N=315) who completed the studies were enrolled into GWPCARE5. In the subgroup of DS patients treated with concomitant clobazam for 37 to 48 weeks (N=147), the median percentage reduction from baseline in convulsive seizure frequency was 64% during Week 1-12 (N=147), which was maintained through to Week 37-48, with a median percentage reduction from baseline in convulsive seizure frequency of 58%.
The efficacy of cannabidiol (25 and 50 mg/kg/day) for the adjunctive therapy of seizures associated with TSC was evaluated in a randomised, double-blind, placebo-controlled, parallel-group study (GWPCARE6). The study consisted of a 4-week baseline period, a 4-week titration period and a 12-week maintenance period (16-week treatment and primary evaluation period).
Mean age of the study population was 14 years and all patients but one were taking one or more concomitant AEDs (cAEDs) during the study. The most commonly used cAEDs (>25% of patients) were valproate (45%), vigabatrin (33%), levetiracetam (29%), and clobazam (27%).
The primary endpoint was the change in number of TSC-associated seizures during the treatment period (maintenance and titration) compared to baseline for the cannabidiol group compared to placebo. TSC-associated seizures were defined as focal motor seizures without impairment of consciousness or awareness; focal seizures with impairment of consciousness or awareness; focal seizures evolving to bilateral generalized convulsive seizures and generalized seizures (tonic–clonic, tonic, clonic or atonic seizures). Key secondary endpoints were the proportion of patients with at least a 50% reduction in TSC-associated seizure frequency, Subject/Caregiver Global Impression of Change at the last visit and the percentage change from baseline in total seizure frequency.
Cannabidiol 50 mg/kg/day was shown to have a similar level of seizure reduction as 25 mg/kg/day. However, this dose was associated with an increased rate of adverse reactions compared to the 25 mg/kg/day and therefore the maximum recommended dose is 25 mg/kg/day.
Table 6 summarises the primary endpoint of percent reduction from baseline in TSC-associated seizures, and the key secondary measure of proportion of patients with at least a 50% reduction in TSC-associated seizure frequency for the maximum recommended dose of 25 mg/kg/day.
Table 6. Primary and ≥50% responder key secondary outcome measures in the TSC study (overall patient population):
| Study GWPCARE6 | ||
|---|---|---|
| Cannabidiol 25 mg/kg/day (n=75) | Placebo (n=76) | |
| Primary endpoint – Percentage reduction in TSC-associated seizure frequencya | ||
| TSC-associated seizures % Reduction from Baseline | 48.6% | 26.5% |
| Percent Reduction Compared with Placebo | ||
| 95% CI P-value | 30.1% 13.9%, 43.3% 0.0009 | |
| Key Secondary endpoint - ≥50% REDUCTION IN TSC-associated seizures (RESPONDER ANALYSIS) | ||
| Percentage of patients with a ≥50% reduction P-valueb | 36% 0.0692 | 22.4% |
CI=95% confidence interval.
a Data for study GWPCARE6 are presented as percent reduction from baseline estimated from a negative binomial regression analysis.
b The Overall p-value is based on a Cochran Mantel Haenszel test.
In the GWPCARE6 study, 22.7% of TSC patients in the 25 mg/kg/day group and 32.9% in the placebo group were taking concomitant clobazam. Results of subgroup analysis by clobazam use showed additive anticonvulsant effects of cannabidiol in the presence of clobazam.
In the subgroup of patients treated with concomitant clobazam, patients receiving cannabidiol 25 mg/kg/day experienced a 61.1% reduction from baseline in TSC-associated seizure frequency compared to a 27.1% reduction in the placebo group, based on a negative binomial regression analysis. Compared with placebo, cannabidiol was associated with a 46.6% reduction (nominal p=0.0025) in TSC-associated seizures (95% CI: 20.0%, 64.4%).
In the subgroup of patients treated without concomitant clobazam, patients receiving cannabidiol 25 mg/kg/day experienced a 44.4 % reduction from baseline in TSC-associated seizure frequency compared to a 26.2% reduction in the placebo group; based on a negative binomial regression analysis. Compared with placebo, cannabidiol was associated with a 24.7% reduction (nominal p=0.0242) in TSC-associated seizures (95% CI: 3.7%, 41.1%).
Cannabidiol was associated with an increase in the percentage of subjects (16.0%) experiencing a greater than or equal to 75% reduction in TSC-associated seizure frequency during the treatment period compared with the placebo group (0%).
Patients receiving cannabidiol experienced a greater percentage reduction in total seizures (48.1%) compared with placebo (26.9%).
Global Impression of Change scores at the last visit were reported by caregivers and patients. 68.6% of patients in the cannabidiol group vs. 39.5% in the placebo group experienced an improvement.
Compared with placebo, cannabidiol was associated with an increase in the number of TSC-associated seizure free days during the treatment period, equivalent to 2.82 days per 28 days.
The effect of cannabidiol on infantile/epileptic spasms associated with TSC has not been fully assessed.
Of the 201 patients who completed the GWPCARE6 study, 99.0% (199 patients) were enrolled into the OLE study. In the OLE the median percentage reduction from baseline in TSC-associated seizure frequency was 61% during Week 1–12 (N=199), which was maintained through to Week 37–48, with a median percentage reduction from baseline in TSC-associated seizure frequency of 68%.
In a human abuse potential study, acute administration of cannabidiol to non-dependent adult recreational drug users at therapeutic and supratherapeutic doses produced small responses on positive subjective measures such as Drug Liking and Take Drug Again. Compared to dronabinol (synthetic THC) and alprazolam, cannabidiol has low abuse potential.
The European Medicines Agency has deferred the obligation to submit the results of studies with cannabidiol in one or more subsets of the paediatric population in treatment of seizures associated with DS, LGS and TSC. (See section 4.2 for information on paediatric use).
The GWPCARE6 study, conducted in patients with TSC, included 8 children between 1 and 2 years of age across all treatment groups. Although data are limited, the observed treatment effect and tolerability were similar to that seen in patients of 2 years of age and older, however, efficacy, safety and pharmacokinetics in children <2 years of age have not been established (see section 4.2).
Cannabidiol appears rapidly in plasma with a time to maximum plasma concentration of 2.5–5 hours at steady state.
Steady-state plasma concentrations are attained within 2-4 days of twice daily dosing based on pre-dose (Ctrough) concentrations. The rapid achievement of steady state is related to the multiphasic elimination profile of the drug in which the terminal elimination represents only a small fraction of the drug’s clearance.
In healthy volunteer studies, co-administration of cannabidiol (750 or 1500 mg) with a high-fat/high calorie meal increased the rate and extent of absorption (5-fold increase in Cmax and 4-fold increase in AUC) and reduced the total variability of exposure compared with the fasted state in healthy volunteers. Although the effect is slightly smaller for a low-fat/low-calorie meal, the elevation in exposure is still marked (Cmax by 4-fold, AUC by 3-fold). Furthermore, taking cannabidiol with bovine milk enhanced exposure by approximately 3-fold for Cmax and 2.5-fold for AUC. Taking cannabidiol with alcohol also caused enhanced exposure to cannabidiol, with a 63% greater AUC.
In the randomised controlled trials, the timing of dose of cannabidiol with respect to meal times was not restricted. In patients, a high fat meal was also shown to increase the bioavailability of cannabidiol (3-fold). This increase was moderate when the prandial state was not fully known, i.e., 2.2-fold increase of the relative bioavailability.
To minimise the variability in the bioavailability of cannabidiol in the individual patient, administration of cannabidiol should be standardised in relation to food intake including a ketogenic diet (high-fat meal) i.e., Epidyolex should be taken consistently with or without food. When taken with food, a similar composition of food should be considered, if possible.
In vitro, >94% of cannabidiol and its phase I metabolites were bound to plasma proteins, with preferential binding to human serum albumin.
The apparent volume of distribution after oral dosing was high in healthy volunteers at 20,963 L to 42,849 L and greater than total body water, suggesting a wide distribution of cannabidiol.
The half-life of cannabidiol in plasma was 56–61 hours after twice daily dosing for 7 days in healthy volunteers.
Cannabidiol is extensively metabolised by the liver via CYP450 enzymes and the UGT enzymes. The major CYP450 isoforms responsible for the phase I metabolism of cannabidiol are CYP2C19 and CYP3A4. The UGT isoforms responsible for the phase II conjugation of cannabidiol are UGT1A7, UGT1A9 and UGT2B7.
Studies in healthy subjects showed there were no major differences in the plasma exposure to cannabidiol in CYP2C19 intermediate and ultra-rapid metabolisers when compared to extensive metabolisers.
The phase I metabolites identified in standard in vitro assays were 7-COOH-CBD, 7-OH-CBD, and 6-OH-CBD (a minor circulating metabolite).
After multiple dosing with cannabidiol, the 7-OH-CBD metabolite (active in a preclinical model of seizure) circulates in human plasma at lower concentrations than the parent drug cannabidiol (~40% of CBD exposure) based on AUC.
The plasma clearance of cannabidiol following a single 1500 mg dose of cannabidiol is about 1,111 L/h. Cannabidiol is predominantly cleared by metabolism in the liver and gut and excreted in faeces, with renal clearance of parent drug being a minor pathway.
Cannabidiol does not interact with the major renal and hepatic transporters in a way that is likely to result in relevant drug-drug interactions.
The Cmax and AUC of cannabidiol are close to dose-proportional over the therapeutic dose range (10-25 mg/kg/day). After single dosing, exposure over the range 750-6000 mg increases in a less than dose-proportional manner, indicating that absorption of cannabidiol may be saturable. Multiple dosing in TSC patients also indicated that absorption is saturable at doses above 25 mg/kg/day.
Population pharmacokinetic analyses demonstrated that there were no clinically relevant effects of age, body weight, sex, or race on exposure to cannabidiol.
Pharmacokinetics of cannabidiol have not been studied in subjects >74 years of age.
Pharmacokinetics of cannabidiol have not been studied in paediatric patients <2 years of age.
A small number of patients <2 years with treatment-resistant epilepsy (including TSC, LGS and DS) have been exposed to cannabidiol in clinical trials and in an expanded access programme.
No effects on the Cmax or AUC of cannabidiol were observed following administration of a single dose of cannabidiol 200 mg in subjects with mild, moderate, or severe renal impairment when compared to patients with normal renal function. Patients with end-stage renal disease were not studied.
No effects on cannabidiol or metabolite exposures were observed following administration of a single dose of cannabidiol 200 mg in subjects with mild hepatic impairment.
Subjects with moderate and severe hepatic impairment showed higher plasma concentrations of cannabidiol (approximately 2.5-5.2-fold higher AUC compared to healthy subjects with normal hepatic function). Cannabidiol should be used with caution in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment. The dose titration should be performed as detailed in section 4.2.
In patients with LGS, population pharmacokinetic pharmacodynamic (PK/PD) modelling indicated the presence of an exposure efficacy relationship for the likelihood of achieving a ≥50% reduction in drop seizure frequency across the cannabidiol dose range tested (0 [placebo], 10 and 20 mg/kg/day). There was a significant positive correlation between the derived AUC of cannabidiol and the probability of a ≥50% response. The responder rate analysis also showed a correlation in the exposure–response relationship for the active metabolite of cannabidiol (7-OH-CBD). PK/PD analysis also demonstrated that systemic exposures to cannabidiol were correlated with some adverse events namely elevated ALT, AST, diarrhoea, fatigue, GGT, loss of appetite, rash, and somnolence (see section 4.8). Clobazam (separate analysis) was a significant covariate which caused the probability of GGT to increase, loss of appetite to decrease, and somnolence to increase.
In TSC patients there is no exposure-response relationship based on efficacy endpoints, as the doses evaluated are at the high end of the dose-response relationship. However, an exposure-response relationship was determined for the 7-OH-CBD metabolite in relation to AST elevation. No other PK/PD relationships with safety endpoints were identified for CBD or its metabolites.
Cannabidiol is a substrate for CYP3A4, CYP2C19, UGT1A7, UGT1A9 and UGT2B7.
In vitro data suggest that cannabidiol is an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT1A9 and UGT2B7 activity at clinically relevant concentrations. The metabolite 7-carboxy-cannabidiol (7-COOH-CBD) is an inhibitor of UGT1A1, UGT1A4 and UGT1A6-mediated activity, in vitro at clinically relevant concentrations (see also section 4.5).
Inhibition of P-gp mediated efflux by cannabidiol in the intestine cannot be ruled out.
Cannabidiol induces CYP1A2 and CYP2B6 mRNA expression at clinically relevant concentrations.
Cannabidiol and the metabolite 7-OH-CBD do not interact with the major renal or hepatic uptake transporters and therefore are unlikely to result in relevant drug-drug interactions: OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, OATP1B1and OATP1B3. Cannabidiol is not a substrate for or an inhibitor of the brain uptake transporters OATP1A2 and OATP2B1. Cannabidiol and 7-OH-CBD are not substrates for or inhibitors of efflux transports P-gp/MDR1, BCRP or BSEP at clinically relevant plasma concentrations. The metabolite 7-COOH-CBD is a P-gp/MDR1 substrate and has the potential to inhibit BCRP, OATP1B3, and OAT3.
Drug interaction studies with AEDs
Potential interactions between cannabidiol (750 mg twice daily in healthy volunteers and 20 mg/kg/day in patients) and other AEDs were investigated in drug-drug interaction studies in healthy volunteers and in patients and in a population pharmacokinetic analysis of plasma drug concentrations from placebo-controlled studies in the treatment of patients with LGS.
The combination of cannabidiol with clobazam caused an elevation in exposure to the active metabolite N-desmethylclobazam, with no effect on clobazam levels. Although exposure to cannabidiol was not notably affected by clobazam use, the levels of an active metabolite, 7-OH-CBD, were elevated by this combination. Therefore, dose adjustments of cannabidiol or clobazam may be required. The interactions are summarised in the table below.
Table 7. Drug interactions between cannabidiol and concomitant antiepileptic drugs:
| Concomitant AED | Influence of AED on cannabidiol | Influence of cannabidiol on AED |
|---|---|---|
| Clobazam | No effect on cannabidiol levels. Interaction resulting in an increase in exposure of the active metabolite 7-OH-CBD in HV* studies.a | No effect on clobazam levels. Interaction resulting in approximately 3-fold increase in N-desmethylclobazam metabolite exposure.b |
| Valproate | No effect on CBD or its metabolites. | No effect on valproic acid exposure or exposure to the putative hepatotoxic metabolite 2-propyl-4-pentenoic acid (4-ene-VPA). |
| Stiripentol | No effect on cannabidiol levels. Interaction resulting in a decrease (approximately 30%) in Cmax and AUC of the active metabolite 7-OH-CBD in trials conducted in HV* and patients with epilepsy. | Interaction resulting in an approximate 28% increase in Cmax and 55% increase in AUC in a HV* study and increases of 17% in Cmax and 30% increases in AUC in patients. |
a average increases of 47% in AUC and 73% in Cmax.
b based on Cmax and AUC.
* HV=Healthy Volunteer.
Genotoxicity studies have not detected any mutagenic or clastogenic activity.
No adverse reactions were observed on male or female fertility or reproduction performance in rats at doses up to 250 mg/kg/day (approximately 34-fold greater than the maximum recommended human dose (MRHD) at 25 mg/kg/day).
The embryo-foetal development (EFD) study performed in rabbits evaluated doses of 50, 80, or 125 mg/kg/day. The dose level of 125 mg/kg/day induced decreased foetal body weights and increased foetal structural variations associated with maternal toxicity. Maternal plasma cannabidiol exposures at the no observed-adverse-effect-level (NOAEL) for embryofoetal developmental toxicity in rabbits were less than that in humans at a dosage of 25 mg/kg/day.
In rats, the EFD study evaluated doses of 75, 150, or 250 mg/kg/day. Embryofoetal mortality was observed at the high dose, with no treatment-related effects on implantation loss at the low or mid doses. The NOAEL was associated with maternal plasma exposures (AUC) approximately 9 times greater than the anticipated exposure in humans at a dosage of 25 mg/kg/day.
A pre- and post-natal development study was performed in rats at doses of 75, 150, or 250 mg/kg/day. Decreased growth, delayed sexual maturation, behavioural changes (decreased activity), and adverse effects on male reproductive organ development (small testes in adult offspring) and fertility were observed in the offspring at doses ≥ 150 mg/kg/day. The NOAEL was associated with maternal plasma cannabidiol exposures approximately 5 times that in humans at a dosage of 25 mg/kg/day.
In juvenile rats, administration of cannabidiol for 10 weeks (subcutaneous doses of 0 or 15 mg/kg on postnatal days [PNDs] 4-6 followed by oral administration of 0, 100, 150, or 250 mg/kg on PNDs 7-77 resulted in increased body weight, delayed male sexual maturation, neurobehavioural effects, increased bone mineral density, and liver hepatocyte vacuolation. A no-effect dose was not established. The lowest dose causing developmental toxicity in juvenile rats (15 mg/kg subcutaneous/100 mg/kg oral) was associated with cannabidiol exposures (AUC) approximately 8 times that in humans at 25 mg/kg/day.
In another study, cannabidiol was dosed to juvenile rats from PND 4-21 (as a subcutaneous injection) and from PND 22-50 (as an intravenous injection). A NOAEL of 15 mg/kg/day was established.
Animal abuse-related studies show that cannabidiol does not produce cannabinoid-like behavioural responses, including generalisation to delta-9-tetrahydrocannabinol (THC) in a drug discrimination study. Cannabidiol also does not produce animal self-administration, suggesting it does not produce rewarding effects.
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