Abstract
Purpose
A Phase I study to assess the single and multipledose pharmacokinetics (PKs) and safety and tolerability of oromucosally administered Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, in healthy male subjects.
Methods
Subjects received either single doses of THC/CBD spray as multiple sprays [2 (5.4 mg THC and 5.0 mg CBD), 4 (10.8 mg THC and 10.0 mg CBD) or 8 (21.6 mg THC and 20.0 mg CBD) daily sprays] or multiple doses of THC/CBD spray (2, 4 or 8 sprays once daily) for nine consecutive days, following fasting for a minimum of 10 h overnight prior to each dosing. Plasma samples were analyzed by gas chromatography-mass spectrometry for CBD, THC, and its primary metabolite 11-hydroxy-THC, and various PK parameters were investigated.
Results
Δ9-Tetrahydrocannabinol and CBD were rapidly absorbed following single-dose administration. With increasing single and multiple doses of THC/CBD spray, the mean peak plasma concentration (Cmax) increased for all analytes. There was evidence of dose-proportionality in the single but not the multiple dosing data sets. The bioavailability of THC was greater than CBD at single and multiple doses, and there was no evidence of accumulation for any analyte with multiple dosing. Inter-subject variability ranged from moderate to high for all PK parameters in this study. The time to peak plasma concentration (Tmax) was longest for all analytes in the eight spray group, but was similar in the two and four spray groups. THC/CBD spray was well-tolerated in this study and no serious adverse events were reported.
Conclusions
The mean Cmax values (<12 ng/mL) recorded in this study were well below those reported in patients who smoked/inhaled cannabis, which is reassuring since elevated Cmax values are linked to significant psychoactivity. There was also no evidence of accumulation on repeated dosing.
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Notes
The initial study design included a fasted/fed crossover phase for Group 2 subjects. Here, we focus only on fasted subjects; as such, data were analyzed from data sets collected on Days 1 or 4 from fasted Group 2 subjects.
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Competing interests
GW Pharma Ltd. produces THC/CBD spray and is licensed for the treatment of spasticity in multiple sclerosis in several European countries. This study was funded by GW Pharma Ltd. D. Wilbraham is an employee of Quintiles Ltd who were contracted to perform the clinical study. C. Stott, L. White, S. Wright and G. Guy are all employees of GW Pharma Ltd, and are shareholders of the company.
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Clinical trial registration
This trial is registered in www.clinicaltrials.gov under registration number NCT01322464.
Sativex, a THC/CBD oromucosal spray, does not have an international nonproprietary name. Nabiximols is the U.S. Adopted Name (USAN).
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Stott, C.G., White, L., Wright, S. et al. A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray. Eur J Clin Pharmacol 69, 1135–1147 (2013). https://doi.org/10.1007/s00228-012-1441-0
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DOI: https://doi.org/10.1007/s00228-012-1441-0