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

Abstract

∆9-Tetrahydrocannabinol (THC) exhibits several therapeutic effects, such as analgesics, anti-emetic, antispastic, and muscle relaxation properties. Knowledge concerning THC disposition in target organs is crucial for THC therapy. The objective of this study was to develop a physiologically-based pharmacokinetic (PBPK) model of THC in humans to characterize tissue-specific pharmacokinetics of THC in organs of interest. The model was extrapolated from the previously developed PBPK model conducted in mice, rats, and pigs. The model consisted of seven compartments: brain, lungs, liver, kidneys, fat, and rapidly perfused and slowly perfused tissues. P-glycoprotein was included in the brain compartment to characterize an efflux of THC from the brain. Physiologic, biochemical, and physicochemical parameters were determined and acquired from the literature. Model validation was performed by comparisons of the predicted and observed THC concentrations acquired from published studies. The developed PBPK model resulted in good agreement between the predicted and observed THC concentrations across several studies conducted following IV bolus, IV infusion, oral, and smoking and inhalation, with the coefficient of determination (R2) ranging from 0.54 to 0.95. A PBPK model of THC in humans was developed. The model could describe THC concentration-time profiles in several dosing scenarios (i.e., IV bolus, IV infusion, oral administration and inhalation).