A Phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers

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

Development of a Novel Nano­emulsion Formulation to Improve Intestinal Absorption of Cannabidiol

“…In this study, AUC 0– ∞ and C max following oral administration of CBD oil were similar to the results of previously published studies [26, 27, 30, 36]. The present results demonstrated that the novel CBD-NE formulation improved the bioavailability of CBD (AUC 0– ∞ /dose) by approximately 65%, although this change was not significant.…”

“…Several studies showed that the metabolism of CBD in rats was different from that in humans [36, 42, 43], suggesting that the human-rat difference in the absolute bioavailability (i.e., very low in humans but moderate in rats) may be due to the lower first-pass metabolism of CBD in rats. Considering a future clinical study, where the present CBD-NE formulation is orally administered and its pharmacokinetic profile is compared with a conventional oil solution in humans, we could expect the increment of the CBD bioavailability by nanoemulsification to be higher than that observed in the present study (65%).…”

The therapeutic use of cannabinoids: Forensic aspects

“…On the basis of the data of literature, Nabiximol can be detected in the blood after few minutes from its administration. C max ranges between 2.5-2.94 ng/ml after an administration of 10.8 mg of Δ 9 -THC (four puffs of Nabiximol) [18]. The onset of pharmacological activity is reported from 15 to 40 min.…”

Cannabis use during pregnancy: Pharmacokinetics and effects on child development

“…11-OH-Δ 9 -THC is even more pharmacologically active than THC (Christensen et al, 1971) but the activity of 8-OH-THC is not known. In vitro and in vivo data suggest that 11-OH-THC is formed predominantly by CYP2C9 while 8-OH-THC is mainly formed by CYP3A4 (Bland et al, 2005; Bornheim et al, 1992; Stott et al, 2013; Watanabe et al, 2007). The 11-nor-THC-COOH is formed from 11-OH-THC by microsomal alcohol dehydrogenase enzymes (Narimatsu et al, 1988).…”