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

BACKGROUND AND OBJECTIVE: ∆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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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).

Development of a Physiologically-Based Pharmacokinetic Model of Δ9-Tetrahydrocannabinol in Mice, Rats, and Pigs.

BACKGROUND AND OBJECTIVE: There has been an increase in the use of cannabis. Delta-9-tetrahydrocannabinol, (THC) is the major psychoactive compound, which has both therapeutic and narcotic effects. THC pharmacokinetics are important for designing optimal dosing regimens, and physiologically-based pharmacokinetic (PBPK) models are used to predict a compound's actions in target organs. Extrapolation of the model from animals to humans can be applied for predicting THC exposure in humans. Here, we aimed to develop a PBPK model of THC in mice, rats, and pigs. METHODS: A PBPK model of THC in mice, rats, and pigs was developed based on seven compartments, i.e., lungs, brain, fat, kidneys, liver, and rapidly perfused and slowly perfused tissues. A flow-limited model was employed to explain THC distribution across tissues. Physiological parameters (i.e., organ blood flows and organ volumes, and biochemical as well as physicochemical parameters, were acquired from the literature. Qualification of the model was assessed based on agreement between simulated and observed THC concentrations. RESULTS: The developed PBPK model consisted of the seven compartments with P-glycoprotein involvement in the brain satisfactorily explained the observed data acquired from three studies. Although some under- and over-predictions exist, the model adequately captured the behavior of the observed data from all three species, with the coefficient of determination (R2) ranging from 0.47 to 0.99. CONCLUSIONS: A PBPK model of THC in mice, rats, and pigs was successfully developed and validated. This model can be further applied for inter-species extrapolation to humans.