Novel Δ(9) -tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects

Abstract

What is already known about this subject: • Cannabis based medicines are registered as a treatment for various indications, such as pain and spasms in multiple sclerosis (MS) patients, and anorexia and nausea in patients with HIV or receiving cancer treatment. • the pharmacokinetics of the various administration routes of cannabis and cannabis based medicines are variable and dosing is hard to regulate.

What this study adds: • Namisol is a new tablet containing pure THC (>98%) that has a beneficial pharmacokinetic profile after oral administration. • Namisol gives a quick onset of pharmacodynamic effects in healthy volunteers, which implies a rapid initiation of therapeutic effects in patients.

Aims: Among the main disadvantages of currently available Δ(9) -tetrahydrocannabinol (THC) formulations are dosing difficulties due to poor pharmacokinetic characteristics. Namisol® is a novel THC formulation, designed to improve THC absorption. The study objectives were to investigate the optimal administration route, pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of Namisol®.

Methods: This first in human study consisted of two parts. Panel I included healthy males and females (n = 6/6) in a double-blind, double-dummy, randomized, crossover study with sublingual (crushed tablet) and oral administration of Namisol® (5 mg THC). Based on these results, male and female (n = 4/5) participants from panel I received oral THC 6.5 and 8.0 mg or matching placebo in a randomized, crossover, rising dose study during panel II. PD measurements were body sway; visual analogue scales (VAS) mood, psychedelic and heart rate. THC and 11-OH-THC population PK analysis was performed.

Results: Sublingual administration showed a flat concentration profile compared with oral administration. Oral THC apparent t(1/2) was 72-80 min, t(max) was 39-56 min and C(max) 2.92-4.69 ng ml(-1) . THC affected body sway (60.8%, 95% CI 29.5, 99.8), external perception (0.078 log mm, 95% CI 0.019, 0.137), alertness (-2.7 mm, 95% CI -4.5, -0.9) feeling high (0.256 log mm, 95% CI 0.093, 0.418) and heart rate (5.6 beats min(-1) , 95% CI 2.7, 6.5). Namisol® was well tolerated.

Conclusions: Oral Namisol® showed promising PK and PD characteristics. Variability and t(max) of THC plasma concentrations were smaller for Namisol® than reported for studies using oral dronabinol and nabilone. This study was performed in a limited number of healthy volunteers. Therefore, future research on Namisol® should study clinical effects in patient populations.

Figure 1

THC (A) and 11-OH-THC (B) concentrations after sublingual 5.0 mg and oral 5.0, 6.5 and 8.0 mg Namisol® administration as estimated with a mixed model. Closed circles are sublingual THC 5.0 mg, open circles are oral THC 5.0 mg, triangles are oral THC 6.5 mg and squares are oral THC 8.0 mg. Error bars represent SD

Figure 2

Visual predictive checks of THC concentrations after a single dose of THC 5.0, 6.5, and 8.0 mg (A, B and C) and of 11-OH-THC concentrations (D, E, and F). Lower limit of quantification for THC and 11-OH-THC is 0.1 ng ml⁻¹

Figure 3

Stochastic simulations (n = 2000) of concentrations of THC after a single 5 mg dose (A), and after 21 dosages, 5 mg two times per day (B)and simulations of 11-OH-THC concentrations after a single 5 mg dose (C), and after 21 dosages, 5 mg two times per day (D)

Figure 4

Effect−time profiles of baseline corrected body sway least square means in %, with 95% confidence interval error bars. A shows the results from panel I of the study, including sublingual THC 5.0 mg as closed circles and oral THC 5.0 mg as open circles. B has the results of panel II, with oral THC 6.5 mg as triangles and oral THC 8.0 mg as squares