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 (R-2) 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.