Cannabidiol Other names: CBD

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).

Pharmacodynamic effects

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).

Absorption

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 (C_trough) 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 C_max 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 (C_max by 4-fold, AUC by 3-fold). Furthermore, taking cannabidiol with bovine milk enhanced exposure by approximately 3-fold for C_max 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., cannabidiol should be taken consistently with or without food. When taken with food, a similar composition of food should be considered, if possible.

Distribution

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.

Biotransformation and elimination

The half-life of cannabidiol in plasma was 56–61 hours after twice daily dosing for 7 days in healthy volunteers.

Metabolism

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.

Excretion

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.

Linearity

The C_max 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.

Pharmacokinetics in special patient groups

Effect of age, weight, sex, race

Population pharmacokinetic analyses demonstrated that there were no clinically relevant effects of age, body weight, sex, or race on exposure to cannabidiol.

Elderly

Pharmacokinetics of cannabidiol have not been studied in subjects >74 years of age.

Paediatric patients

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.

Renal impairment

No effects on the C_max 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.

Hepatic impairment

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.

Pharmacokinetic/pharmacodynamic relationship(s)

In LGS

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. 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

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.

Drug interaction studies

In vitro assessment of drug interactions

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.

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.

In vivo assessment of drug interactions

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.

Drug interactions between cannabidiol and concomitant antiepileptic drugs:

^a average increases of 47% in AUC and 73% in C_max.
^b based on C_max and AUC.
^* HV=Healthy Volunteer.

Mutagenicity

Genotoxicity studies have not detected any mutagenic or clastogenic activity.

Reproductive toxicity

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.

Juvenile toxicity

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.

Abuse

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.