A Δ⁹-Tetrahydrocannabinol Physiologically-Based Pharmacokinetic Model Development in Humans

Area of Science:

• Pharmacokinetics
• Physiologically-based pharmacokinetic (PBPK) modeling
• Cannabinoid research

Background:

• Delta-9-tetrahydrocannabinol (THC) possesses therapeutic properties including analgesia, anti-emesis, and muscle relaxation.
• Understanding THC distribution in target organs is vital for optimizing THC-based therapies.
• Existing knowledge gaps necessitate advanced modeling for tissue-specific THC disposition.

Purpose of the Study:

• To develop a human physiologically-based pharmacokinetic (PBPK) model for delta-9-tetrahydrocannabinol (THC).
• To characterize tissue-specific pharmacokinetics of THC in key human organs.
• To provide a predictive tool for THC therapy and drug development.

Main Methods:

• Extrapolation of a pre-existing PBPK model from animal studies (mice, rats, pigs) to humans.
• Inclusion of seven distinct physiological compartments (brain, lungs, liver, kidneys, fat, rapidly perfused, and slowly perfused tissues).
• Incorporation of P-glycoprotein in the brain compartment to model THC efflux; parameterization using literature data; validation against published THC concentration data.

Main Results:

• The developed PBPK model demonstrated good agreement between predicted and observed THC concentrations.
• Model validation across multiple studies and administration routes (IV bolus, IV infusion, oral, inhalation) showed high accuracy.
• The coefficient of determination (R²), indicating model fit, ranged from 0.54 to 0.95.

Conclusions:

• A robust PBPK model for THC in humans has been successfully developed.
• The model accurately describes THC concentration-time profiles across various administration routes.
• This PBPK model serves as a valuable tool for predicting THC behavior in different tissues and optimizing therapeutic strategies.