A phase I trial of the safety, tolerability and pharmacokinetics of cannabidiol administered as single-dose oil solution and single and multiple doses of a sublingual wafer in healthy volunteers.

AIMS: This study investigated the safety, tolerability and pharmacokinetics after administration of a specific Cannabis sativa cultivar extract, standardised to cannabidiol (CBD) content as sublingual wafer or oil formulation compared to nabiximols oromucosal spray. METHODS: For the single-dose study, the design was an open-label, 4-way crossover in 12 healthy volunteers randomised to receive a sequence of 4 different single doses of CBD as a sublingual wafer (25 or 50 mg CBD), oil solution (50 mg CBD), or nabiximols oromucosal spray (20 mg CBD, 21.6 mg tetrahydrocannabinol). For the multiple-dose study, sublingual wafer (50 mg CBD) was administered twice a day for 5 days. RESULTS: The extract was generally well tolerated by participants when administered in either wafer or oil form, with some adverse events, including mild or moderate somnolence, sedation and altered mood. The relative bioavailability of CBD after administration as a sublingual wafer was comparable with that of oil solution with 90% confidence interval of 83-131%. The median maximum concentrations of CBD after administration of oil solution and wafer was 9.4 and 11.9 ng mL-1 , respectively. Maximum concentrations of CBD occurred 4 hours after administration, with an estimated terminal elimination half-life of 6 hours. There was no statistically significant difference between the AUC0-τ of CBD after administration of oil solution or wafer compared with nabiximols oromucosal spray. CONCLUSION: Oil solution and sublingual wafer formulations of the extract standardised with CBD were well tolerated and achieved equivalent concentrations of CBD when compared to an available commercial nabiximols formulation.

Population Pharmacokinetics of Oral-Based Administration of Cannabidiol in Healthy Adults: Implications for Drug Development.

Background and Objectives: Cannabidiol (CBD) is increasingly being studied as a therapeutic option for a range of health conditions; however, the pharmacokinetics of CBD is not well understood. This study characterized CBD pharmacokinetics in healthy adults using a population pharmacokinetic approach, informing drug development of oral-based dose forms of CBD. Materials and Methods: CBD concentration-time data were obtained from a phase I, randomized, open-label, four-way crossover study (n=12) and modeled using Phoenix NLME. Monte Carlo simulations were conducted to estimate CBD exposure with chronic dosing as intended for clinical use (50 mg b.i.d.). Results: A three-compartment pharmacokinetic model with a chain of absorption transit compartments and first-order elimination most adequately described CBD pharmacokinetics. Substantial variability in population pharmacokinetic parameters was identified (up to 60%CV), which could not be accounted for by any covariates. Simulations indicated a 3.6-fold difference in drug exposure at steady state with multiple dosing (AUCτ 95% prediction interval: 65.5-138 ng·h/mL), and variability in the time to reach steady state, which was predicted to be up to ∼3 weeks in some individuals (95% prediction interval: 18.6-297 h). Conclusions: The findings of this study have important implications for drug development. The lack of a clear dose-response relationship, due to large pharmacokinetic variability, indicates that a one-size-fits-all approach to CBD dosing may not be feasible, at least with current dosing approaches. Furthermore, an extended time to reach steady state means that the full effect of a selected dose level is not truly observed for some time and requires careful consideration in trial design.