Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic Group: Other Analgesics and Antipyretics
ATC Code: N02BG10
Mechanism of action
As part of the human endocannabinoid system (ECS), cannabinoid receptors, CB1 and CB2 receptors are found predominantly at nerve terminals where they have a role in retrograde regulation of synaptic function. THC acts as a partial agonist at both CB1 and CB2 receptors, mimicking the effects of the endocannabinoids, which may modulate the effects of neurotransmitters (e.g. reduce effects of excitatory neurotransmitters such as glutamate).

In animal models of MS and spasticity CB receptor agonists have been shown to ameliorate limb stiffness and improve motor function. These effects are prevented by CB antagonists, and CB1 knockout mice show more severe spasticity. In the CREAE (chronic relapsing experimental autoimmune encephalomyelitis) mouse model, Sativex produced a dose-related reduction in the hind limb stiffness.

Clinical experience
Sativex has been studied at doses of up to 48 sprays/day in controlled clinical trials of up to 19 weeks duration in more than 1500 patients with MS. In the pivotal trials to assess the efficacy and safety of Sativex for symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis (MS) the primary efficacy measure was a 0 to 10 point Numeric Rating Scale (NRS) on 
which patients indicated the average level of their spasticity related symptoms over the last 24 hours where 0 is no spasticity and 10 is the worst possible spasticity.

In a first Phase 3 placebo controlled trial over a 6-week treatment period the difference from placebo reached statistical significance but the difference between treatments of 0.5 to 0.6 points on the 0-10 point NRS was of questionable clinical relevance. In a responder analysis 40% Sativex and 22% placebo responded to treatment using the criterion of greater than a 30% reduction in NRS score.
A second 14 week Phase 3 study failed to show a significant treatment effect. The difference from placebo on the NRS score was 0.2 points.

It was postulated that a clinically useful treatment effect in some patients might be partly masked by data from non-responders in the analyses of mean changes. In analyses comparing NRS scores with patient global impression of change (PGI), a 19% NRS response was estimated to represent a clinically relevant improvement on the PGI and a response of 28% “much improved” on the PGI. In post hoc exploratory combined analyses of the above two studies, a 4-week trial period using a 20% NRS response threshold was predictive of eventual response defined as a 30% reduction.

A third Phase 3 trial incorporated a formalised 4-week therapeutic trial period prior to randomisation.
The aim of the trial was to assess the benefit of continued treatment for patients who achieve an initial response to treatment. 572 patients with MS and refractory spasticity all received single blind Sativex for four weeks. After four weeks on active treatment 273 achieved a reduction of at least 20% on the spasticity symptom NRS, of which 241 met the entry criteria for randomisation, with a mean change from the start of treatment of -3.0 points on the 10 point NRS. These patients were then randomised to either continue to receive active or switch to placebo for the 12 week double-blind phase, for a total of 16 weeks treatment overall.

During the double-blind phase the mean NRS scores for patients receiving Sativex generally remained stable (mean change from randomisation in NRS score -0.19), while the mean NRS scores for patients switched to placebo increased (mean change in NRS score was +0.64 and median change was +0.29). The difference* between treatment groups was 0.84 (95% CI -1.29, -0.40).
* Difference adjusted for centre, baseline NRS and ambulatory status

Of those patients who had a 20% reduction from screening in NRS score at week 4 and continued in the trial to receive randomised treatment, 74% (Sativex) and 51% (placebo) achieved a 30% reduction at week 16.

The results over the 12-week randomised phase are shown below for the secondary endpoints. The majority of secondary endpoints showed a similar pattern to the NRS score, with patients who continued to receive Sativex maintaining the improvement seen from the initial 4-week treatment period, while patients switching to placebo declined:

Modified Ashworth Score                 Sativex -0.1; Placebo +1.8;
for spasticity:                         Adjusted Difference -1.75 (95% CI -3.80, 0.30) 
Spasm frequency (per day):              Sativex -0.05; Placebo +2.41
Adjusted Difference -2.53 (95% CI -4.27, -0.79)

Sleep disruption by spasticity:         Sativex -0.25; Placebo +0.59; (0 to 10 NRS)                           Adjusted Difference -0.88 (95% CI -1.25, -0.51) 
Timed 10 metre walk (seconds):          Sativex -2.3; Placebo +2.0;
Adjusted Difference -3.34 (95% CI -6.96, 0.26)

Motricity index (arm and leg):          No differences between treatment groups were seen.
Barthel Activities of Daily Living:     Odds ratio for improvement: 2.04 
Subject global impression of change (OR=1.71), carer global impression of change (OR=2.40) and physician global impression of change (OR=1.96) all showed statistically significant superiority of Sativex over placebo.

The benefit of continued treatment in the long-term was studied in a placebo controlled, parallel group, randomised withdrawal trial in subjects taking long-term Sativex. Thirty six patients with a mean duration of Sativex use prior to the trial of 3.6 years were randomised to either continue with Sativex treatment or switch to placebo for 28 days. The primary endpoint was time to treatment failure, defined as the time from the first day of randomised treatment to a 20% increase in NRS or premature withdrawal from randomised treatment. Treatment failure was experienced by 44% of Sativex patients, and 94% of placebo patients, hazard ratio 0.335 (95% CI 0.16, 0.69).
In a study designed to identify its abuse potential, Sativex at a dose of 4 sprays taken at one time did not differ significantly from placebo. Higher doses of Sativex of 8 to 16 sprays taken at one time did show abuse potential comparable to equivalent doses of dronabinol, a synthetic THC. In a QTc study a dose of Sativex 4 sprays over 20 minutes twice daily was well-tolerated, but a substantially supratherapeutic dose of 18 sprays over 20 minutes twice daily resulted in significant psychoactivity and cognitive impairment.

Paediatric population
The efficacy and safety of Sativex was evaluated in a 12-week randomised, double-blind, placebo- controlled study involving 72 children and adolescents aged from 8–18 years with cerebral palsy or traumatic central nervous system injury. The placebo controlled phase was followed by a 24-week open label extension phase. The maximum permitted daily dose in this trial was 12 sprays and was titrated for 9 weeks. At baseline, most patients had severe impairment of motor function (Gross Motor Function Classification Scale level IV or V). The primary efficacy endpoint was the change in spasticity severity 0–10 numerical rating scale (NRS) score from baseline which is a carer reported outcome measure.
After 12 weeks of treatment, the mean change from baseline for Sativex-treated participants’ spasticity severity NRS scores was −1.850 (SD 1.9275) and for placebo participants −1.573 (SD 2.0976). The least square mean difference between the two groups (−0.166, 95% CI −1.119, 0.787) was not statistically significant (p=0.7291).
No new safety findings were identified in this study.
No data are available in children below 8 years (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Following administration of Sativex (four sprays), both THC and CBD are absorbed fairly rapidly and appear in the plasma within 15 minutes after single oromucosal administration. With Sativex, a mean Cmax of about 4 ng/mL was reached some 45-120 minutes after a single dose administration of a 10.8 mg THC dose, and was generally well tolerated with little evidence of significant psychoactivity.

When Sativex is co-administered with food the mean Cmax and AUC for THC were 1.6- and 2.8-fold higher compared with fasting conditions. Corresponding parameters for CBD increased 3.3- and 5.1- fold.

There is a high degree of variability in pharmacokinetic parameters between patients. Following a single dose administration of Sativex (four sprays) under fasted conditions, the mean plasma level of THC showed a 57.3% CV for Cmax (range 0.97-9.34ng/mL) and a 58.5% CV for AUC (range 4.2- 30.84 h*ng/mL). Similarly the %CV for CBD was 64.1% (range 0.24-2.57ng/mL) and 72.5% (range 2.18-14.85 ng/mL) for the same parameters respectively. After nine consecutive days of dosing the %
CV values for the same parameters were 54.2% (Cmax range = 0.92-6.37) and 37.4% (AUC0-t = 5.34- 15.01 h*ng/mL) for THC and 75.7% (Cmax range 0.34-3.39 ng/mL) and 46.6% (AUC0-t = 2.40-13.19 h*ng/mL) for CBD respectively.

There is a high degree of variability in pharmacokinetic parameters within patients following single and repeat dosing. Of 12 subjects who received four sprays of Sativex as a single dose, eight had reductions in Cmax after nine days of multiple dosing, whilst three had increases (1 drop-out). For CBD, seven had reductions in Cmax after multiple dosing, whilst four had increases.

When Sativex is administered oromucosally, plasma levels of THC and other cannabinoids are lower compared with the levels achieved following inhalation of cannabinoids at a similar dose. A dose of 8 mg of vaporised THC extract, administered by inhalation resulted in mean plasma Cmax of more than 100 ng/mL within minutes of administration, with significant psychoactivity.

Table to show PK parameters for Sativex, for vaporised THC extract and smoked cannabis 
Cmax THC               Tmax THC             AUC (0-t) THC ng/mL                  minutes              ng/mL/min
Sativex                         5.40                    60                    1362 (providing 21.6 mg THC)
Inhaled vaporised THC           118.6                  17.0                   5987.9 extract (providing 8 mg
THC)
Smoked cannabis*                162.2                  9.0                   No data (providing 33.8 mg THC)

*Huestis et al, Journal of Analytical Toxicology 1992; 16:276-82.

Distribution
As cannabinoids are highly lipophilic, they are quickly absorbed and distributed into body fat. The resultant concentrations in the blood following oromucosal administration of Sativex are lower than those obtained by inhaling the same dose of THC because absorption is slower and redistribution into fatty tissues is rapid. Additionally some of the THC undergoes hepatic first pass metabolism to 11- OH-THC, the first metabolite of THC which then undergoes further oxidation to 11-nor-9-COOH- THC, the most abundant metabolite of THC, and CBD similarly to 7-OH-CBD. Protein binding of THC is high (~97%). THC and CBD may be stored for as long as four weeks in the fatty tissues from which they are slowly released at sub-therapeutic levels back into the blood stream, then metabolised and excreted via the urine and faeces.

Metabolism
THC and CBD are metabolised in the liver. Additionally some of the THC undergoes hepatic first pass metabolism to 11-OH-THC, the primary metabolite of THC, which then undergoes further oxidation to 11-nor-9-COOH-THC, the most abundant metabolite of THC, and CBD similarly to 7- OH-CBD. Human hepatic P450 2C9 isozyme catalyses the formation of 11-OH-THC, the primary metabolite, which is further metabolised by the liver to other compounds including 11-nor-carboxy-9- THC (THC-COOH), the most abundant metabolite in human plasma and urine. The P450-3A subfamily catalyses the formation of other hydroxylated minor metabolites. CBD is extensively metabolised and more than 33 metabolites have been identified in urine. The major metabolic route is hydroxylation and oxidation at C-7 followed by further hydroxylation in the pentyl and propenyl groups. The major oxidized metabolite identified is CBD-7-oic acid containing a hydroxyethyl side chain.

See section 4.5 for information on drug interaction and metabolism by the cytochrome P450 enzyme system.

Transporters
In vitro, Sativex did not inhibit the following transporters at clinically relevant concentrations: BCRP, BSEP, OAT1, OAT3, OCT2, MATE1, MATE2-K, OATP1B1, OATP1B3, OCT1, MATE1 and P-glycoprotein.

Elimination
From clinical studies with Sativex, a non-compartmental PK analysis shows that the first order terminal elimination half life from plasma is 1.94, 3.72 and 5.25 hours for THC and 5.28, 6.39 and 9.36 for CBD following the administration of 2, 4 and 8 sprays respectively.

From the literature, elimination of oral cannabinoids from plasma is bi-phasic with an initial half-life of approximately four hours, and the terminal elimination half-lives are of the order of 24 to 36 hours or longer. Cannabinoids are distributed throughout the body; they are highly lipid soluble and accumulate in fatty tissue. The release of cannabinoids from fatty tissue is responsible for the prolonged terminal elimination half-life.

In a specific hepatic impairment PK study a single oromucosal dose of 4 sprays of Sativex (10.8 mg THC and 10 mg CBD) showed no significant difference in THC or CBD clearance between subjects with mild hepatic impairment and healthy controls. However there was substantially reduced clearance and prolonged elimination half-life in the cohorts of subjects with moderate and severe hepatic impairment.