Abstract
This Phase I study aimed to assess the potential drug-drug interactions (pharmacokinetic [PK] and safety profile) of Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (Sativex ®, nabiximols) in combination with cytochrome P450 (CYP450) inducer (rifampicin) or inhibitors (ketoconazole or omeprazole).Thirty-six healthy male subjects were divided into three groups of 12, and then randomized to one of two treatment sequences per group. Subjects received four sprays of THC/CBD (10.8/10 mg) alongside single doses of the CYP3A and 2C19 inducer rifampicin (600 mg), CYP3A inhibitor ketoconazole (400 mg) or CYP2C19 inhibitor omeprazole (40 mg). Plasma samples were analyzed for CBD, THC and its metabolite 11-hydroxy-THC (11-OH-THC).A single dose of four sprays of THC/CBD spray (10.8/10 mg) following repeated doses of rifampicin (600 mg) reduced the Cmax and AUC of all analytes. Cmax reduced from 2.94 to 1.88 ng/mL (-36%), 1.03 to 0.50 ng/mL (-52%) and 3.38 to 0.45 ng/mL (-87%) for THC, CBD and 11-OH-THC, respectively compared to single dose administration of THC/CBD spray alone. Ketoconazole co-administration with THC/CBD spray had the opposite effect, increasing the Cmax of the respective analytes from 2.65 to 3.36 ng/mL (+27%), 0.66 to 1.25 ng/mL (+89%) and 3.59 to 10.92 ng/mL (+204%). No significant deviations in Cmax or AUC for any analyte were observed when THC/CBD spray was co-administered with omeprazole. THC/CBD spray was well tolerated by the study subjects both alone and in combination with rifampicin, ketoconazole and omeprazole.Evaluation of the PKs of THC/CBD spray alone and in combination with CYP450 inhibitors/inducers suggests that all analytes are substrates for the isoenzyme CYP3A4, but not CYP2C19. On the basis of our findings, there is likely to be little impact on other drugs metabolized by CYP enzymes on the PK parameters of THC/CBD spray, but potential effects should be taken into consideration when co-administering THC/CBD spray with compounds which share the CYP3A4 pathway such as rifampicin or ketoconazole.Trials registrationNCT01323465
Highlights
The endocannabinoid system modulator Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (Sativex®, nabiximols) has been reported to be effective in relieving a number of multiple sclerosis (MS) symptoms including spasticity, central neuropathic pain and bladder dysfunction (Rog et al 2005; Johnson et al 2010; Rog et al 2007), and has recently been approved in various European countries and abroad as add-on treatment for spasticity in MS patients
This study investigated the effects of the known cytochrome P450 (CYP450) inhibitors or inducers rifampicin, ketoconazole and omeprazole, on the PK and safety profiles of THC/CBD spray
The CYP3A4 inducer rifampicin caused a decrease in exposure to all three analytes, not extreme and within the natural range of variation between subjects
Summary
The endocannabinoid system modulator Δ9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (Sativex®, nabiximols) has been reported to be effective in relieving a number of multiple sclerosis (MS) symptoms including spasticity, central neuropathic pain and bladder dysfunction (Rog et al 2005; Johnson et al 2010; Rog et al 2007), and has recently been approved in various European countries and abroad (i.e. in Canada, Israel, New Zealand) as add-on treatment for spasticity in MS patients. The specified CBs constitute at least 90% of the total CB content of the extract, the minor CBs and other constituents contribute to the therapeutic profile of THC/CBD spray (Russo 2011), and may be involved in stabilizing the extract (Whittle et al 2001). CB1 is predominantly expressed in the central nervous system (CNS), while CB2 is primarily expressed in the periphery, especially in immune cells (Pertwee 2007)
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