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

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. CBD concentration-time data were obtained from a phase I, randomized, open-label, four-way crossover study (=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.). 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 (AUC 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). 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.