Predicting Cannabidiol Pharmacokinetics in Older Adults Via Physiologically Based Pharmacokinetic Modeling

Cannabidiol (CBD) use continues to increase, particularly among older adults. However, knowledge of CBD disposition in this ever-growing and understudied population, along with the relative contributions of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes to CBD metabolism, remain limited. Inclusion of UGT activators (e.g., alamethicin, MgCl₂) may alter in vitro estimates of enzyme contributions. CBD has also been reported to produce time-dependent inhibition (TDI) of certain CYPs, potentially affecting its own disposition. We combined in vitro data with physiologically based pharmacokinetic (PBPK) modeling to further characterize TDI and reversible CYP inhibition by CBD, quantify the contributions of CYPs and UGTs to CBD metabolism, and determine in vitro assay conditions that best reflect in vivo CBD metabolism. PBPK modeling was next used to extrapolate CBD exposure from young (18-64 years) to older (65-98 years) adults. CBD exhibited TDI only toward CYP1A2, which had a negligible effect on CBD metabolism. Inclusion of alamethicin + MgCl₂ increased the apparent contribution by UGTs to CBD metabolism, leading to an overestimate of UGT-mediated metabolism. PBPK model validation using drug-drug interaction studies supported contributions of 86% and 14% for CYPs and UGTs, respectively, as best capturing observed CBD exposure. Simulations in older adults generally showed increased CBD exposure relative to young adults, with the magnitude depending on age and administration route. Overall, these results improve our understanding of CBD pharmacokinetics, support more informed risk assessment in older adults, and provide a more robust foundation for future studies.