A Phase I, Open Label, Four-Way Crossover Study to Compare the Pharmacokinetic Profiles of a Single Dose of 20 mg of a Cannabis Based Medicine Extract (CBME) Administered on 3 Different Areas of the Buccal Mucosa and to Investigate the Pharmacokinetics of CBME per Oral in Healthy Male and Female Volunteers (GWPK0112)

This Phase I, open label, four-way crossover study pertains to pharmacokinetic parameters of four cannabis based medicine extracts (CBME). Sublingual, buccal and oro-pharyngeal test treatments 80(GW-1000-02) consisted of 25 mg cannabidiol (CBD) + 25 mg Δ⁹-tetra-hydrocannabinol (THC) per ml formulated in ethanol (eth):propylene glycol (PG) (50:50), with peppermint flavouring with a 100 µl actuation volume (total dose 10 mg CBD + 10 mg THC in 4 actuations). An oral capsule contained 2.5 mg CBD + 2.5 mg THC sprayed onto granulated lactose and encapsulated in soft gelatin capsules (total dose of 10 mg CBD + 10 mg THC 4 capsules). This study was performed in healthy volunteers in an open label, 4 period, 3-way randomised crossover followed by a non-randomised oral dose using single doses of 20 mg of CBME (10 mg CBD + 10 mg THC). In Periods 1 to 3, the test treatment was administered as a liquid spray according to the randomisation scheme (i.e., sublingually, buccally, oro-pharyngeally). In Period 4 the test treatment was delivered as an oral capsule. There was a six-day washout between each dose.

Primary objectives were to compare the pharmacokinetic profiles of cannabis based medicine extract (CBME) when administered on different areas of the buccal mucosa. Secondary objectives were to investigate the pharmacokinetic profile of CBME when administered as an oral capsule.

Concentrations of THC were higher than the corresponding levels of CBD at most time points. Concentrations of 11-hydroxy-THC exceeded the corresponding concentration of THC at most time points. By 720 min (12 h) post-dose, mean concentrations of each cannabinoid were still above the lower limit of quantification (LLOQ). There was a high degree of inter-subject and intra-subject variability in the plasma concentrations achieved.

T_max of CBD and THC occurred earlier following sublingual administration than oro-pharyngeal or buccal although only the difference in T_max of CBD compared with buccal was statistically significant. C_max of both CBD and THC was greatest following buccal administration although this was not statistically significant. AUC was greatest following oro-pharyngeal and was statistically significantly greater than buccal. The lower bioavailability, as measured by AUC, following buccal administration when compared to the sublingual and oro-pharyngeal routes may be related to the difficulty of spraying onto the inside of the cheek reported during the study and could be due to some loss of spray. Buccal administration of the pump action sublingual spray (PASS) test treatment resulted in a later T_max but greater C_max when compared to the sublingual and oro-pharyngeal routes. Comparison of the sublingual and oro-pharyngeal routes showed no statistically significant difference in THC or CBD pharmacokinetic parameters other than an earlier T_max fol-lowing sublingual dosing. The oral capsule appeared to show an early T_max of both CBD and THC. Mean C_max of THC and 11-hydroxy-THC were greater, but in contrast the C_max of CBD was lower, than following 81the PASS treatments. Relative to THC, the plasma level AUC of 11-hydroxy-THC was proportionally greatest following oral capsules which could be a reflection of greater metabolism by this route. Of the PASS treatments the ratio of 11-hydroxy-THC to THC was greatest following sublingual and least following oro-pharyngeal. There was very wide inter- and to a lesser extent intra-subject variability in pharmacokinetics. Differences in mean values between the routes of administration, even when statistically significant, are small relative to the very wide range of values between subjects. The sublingual and oro-pharyngeal routes of administration appear to have the same pharmacokinetic results. The buccal pharmacokinetic parameters are lower when compared to the sublingual and oro-pharyngeal routes.

A total of 146 adverse events (AEs) occurred in 12 subjects. Two events were classified as moderate (flu-like illness and pharyngeal irritation) and the remaining 144 were classified as mild. All routes of administration were well tolerated by all subjects with no serious AEs and no withdrawals due to AEs.

The overall results indicate that administration of the liquid spray (GW-1000-02) need not be limited to sublingual administration. The oral capsule, has good bioavailability, and provided, as is the case here the formulation is not oil based, may be a viable formulation when self-titration is not necessary. [Article copies available for a fee from The Haworth Document Delivery Service: 1-800-HAWORTH. E-mail address: <docdelivery@haworthpress.com> Website: <https://www.HaworthPress.com" xmlns:xlink="https://www.w3.org/1999/xlink">https://www.HaworthPress.com> © 2003 by The Haworth Press, Inc. All rights reserved.]