CFPD-PK Modeling of Inhaled Medical Cannabis: The Role of Puffing Waveform and Holding Time in Delivered Doses

TED SPERRY, Yu Feng, Chen Song, Zhiqiang Shi, Qi Li, Oklahoma State University

     Abstract Number: 54
     Working Group: Health-Related Aerosols

Abstract
Medical cannabis is increasingly used as an alternative therapy for various conditions, including chronic pain, multiple sclerosis, epilepsy, and cancer-related symptoms. However, it is crucial to ensure that patients receive the intended dose of tetrahydrocannabinol (THC) from inhaled cannabis so that the dosing regimen is safe and effective. This requires a comprehensive understanding of the factors that influence the pharmacokinetics (PKs) of THC in the respiratory system. To address this need, this study employed a hybrid computational fluid-particle dynamics (CFPD) and pharmacokinetics (PK) model to evaluate factors that influence delivered doses of THC to the human respiratory system and the resultant THC-plasma concentration-time profile. Specifically, this study compared multiple puff waveforms for inhale-hold-exhale (IHE) with puff volumes from 55 to 82 mL, considering step function velocities, sinusoidal puffs, as well as a measured puff profile. THC deposition in the airways was recorded during all phases for each case using either 452,849 particles per second for the 1.2 µm monodisperse cases or 399,866 per second for the polydisperse cases, with the mass median aerodynamic diameter (MMAD) of 1.2 µm. Regional deposition data is predicted using CFPD for four airway regions, then scaled by region-specific bioavailability factors. The deposited mass in airway regions represents the initial mass entering a 3-compartment PK model. Simulation results showed that puff volume, duration, and holding time significantly influence the delivered dose of THC in the respiratory system and the PK profile in plasma. Specifically, the deposition fractions for the 55 mL and 82 mL step-function cases are only 53% and 61% compared to the sinusoidal cases of the same inhalation volumes. Increased inhalation volume from 55 to 82 mL for sinusoidal IHE cases increased deposition by 13.24%. This study shows that the differences between deposited doses can vary by as much as 245%, while predicted peak plasma concentrations and area under the curve (AUC) vary by 126% for these conditions. Differences between deposition fraction and dosage are due to the limited bioavailability of the particles deposited. In conclusion, this study highlights the importance of accurately predicting the delivered dose of inhaled THC and optimizing dosing regimens for medical cannabis use. Furthermore, CFPD-PK simulations need to use realistic particle size distributions to accurately predict the delivered dose of inhaled THC, emphasizing the need for continued research in this area.