Quantifying Heart Rate Changes After Delta-9-Tetrahydrocannabinol Administration Using a PBPK-PD Model in Healthy Adults

<b>Background</b>: As cannabis becomes legal in several U.S. states, the risk of THC-induced tachycardia increases. This study aimed to develop and verify a physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model to assess the impact of THC and its active metabolite, 11-hydroxy-THC (11-OH-THC), on the heart rate of healthy adults. <b>Methods</b>: A PBPK-PD model for intravenous (IV) 11-OH-THC administration was first developed. Secondly, a PBPK-PD model for IV THC, combined with the metabolized 11-OH-THC, was established, verified, and validated. Direct PD models driven by the plasma, brain, and heart concentrations of THC and 11-OH-THC predicted using our previously verified PBPK model were tested for model development. Finally, the risks of tachycardia at a rest condition from various doses of oral and inhaled THC were simulated for 500 individuals aged 18-65 years, with a sex ratio of 1:1 and a baseline heart rate of 70 beats per minute. <b>Results</b>: The PD model was best described by a direct nonlinear E_max model driven by the sum of the total THC and 11-OH-THC concentrations in their effect compartments linked to their heart compartments. In 42 simulated dosing regimens with THC doses ranging from 2 to 69.4 mg, 97% of the observed heart rates or heart rate changes following THC administration fell within the 5th to 95th percentiles of the model-predicted values. Similarly, for two simulated 11-OH-THC IV doses, 93% of the observations fell within this range. Simulations indicated that half of the simulated population would experience tachycardia at doses of 60 mg and 15 mg of THC for oral and inhaled administration, respectively. The simulated risks of tachycardia based on specific conditions should be interpreted with caution. <b>Conclusions</b>: Our verified PBPK-PD model successfully describes the heart rate changes in healthy adults after IV, oral, and inhaled THC administration. This model provides a tool to predict the effects of THC and its primary metabolite on heart rates, offering valuable insights for assessing the risk of tachycardia in both clinical and recreational cannabis use.