Cannabidiol Bioavailability Is Nonmonotonic with a Long Terminal Elimination Half-Life: A Pharmacokinetic...

Area of Science:

• Pharmacokinetics
• Drug Metabolism
• Cannabinoid Research

Background:

• Cannabidiol (CBD) is used orally and via inhalation for various conditions.
• Long-term exposure kinetics and bioavailability of CBD require further characterization.

Purpose of the Study:

• To characterize the long-term pharmacokinetic (PK) profile of CBD.
• To evaluate the nonmonotonic oral bioavailability of CBD.
• To compare oral and inhalation delivery methods for CBD.

Main Methods:

• Utilized human CBD plasma concentration-time data from oral (Epidiolex®) and inhalation studies.
• Applied a four-compartment PK model with Weibull absorption kinetics.
• Used the Cedergreen-Ritz-Streibig model to assess oral bioavailability.

Main Results:

• CBD exhibits extensive tissue distribution with a terminal half-life exceeding 134 hours.
• Oral CBD requires over 70 days to reach steady-state plasma concentrations with once-daily dosing.
• Oral bioavailability is nonmonotonic (inverted U-shaped) in fasted states, influenced by food and hepatic impairment.
• Inhalation delivery bypasses first-pass metabolism, potentially offering efficient and consistent exposure.

Conclusions:

• CBD pharmacokinetics vary with dose due to nonmonotonic bioavailability.
• Inhalation may reduce variability in CBD exposure compared to oral routes.
• Delayed steady-state attainment and prolonged half-life necessitate consideration for long-term CBD dosing strategies.