Predicting Cannabidiol Pharmacokinetics in Older Adults Via Physiologically Based Pharmacokinetic Modeling.

Qian L.; Nguyen A.; Paine M.; Zhou Z. · The AAPS journal · 2026

**Background & Methods** This was a review study employing physiologically based pharmacokinetic (PBPK) modeling combined with in vitro data to characterize cannabidiol (CBD) metabolism and disposition. The research focused on quantifying contributions of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes to CBD metabolism and extrapolating CBD exposure from young adults (18-64 years) to older adults (65-98 years). **Key Findings** • CBD exhibited time-dependent inhibition (TDI) only toward CYP1A2, which produced negligible effects on CBD's own metabolism; PBPK model validation with drug-drug interaction studies supported metabolic contributions of 86% from CYPs and 14% from UGTs as most accurately reflecting observed CBD exposure in vivo. • In vitro assay conditions significantly influenced enzyme contribution estimates; the inclusion of UGT activators (alamethicin and MgCl₂) artificially increased apparent UGT contributions and led to overestimation of UGT-mediated metabolism compared to clinically observed data. • Simulations in older adults (65-98 years) generally demonstrated increased CBD exposure relative to young adults (18-64 years), with magnitude of elevation dependent on patient age and route of administration, providing important considerations for dose individualization in this population. **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** This review and PBPK modeling study provides medium-level evidence with several limitations. As a modeling-based approach rather than a primary clinical trial, findings represent computational predictions that require clinical validation. The study's strength lies in systematic integration of in vitro data with physiological parameters to characterize enzyme kinetics and age-related pharmacokinetic changes. Key limitations include reliance on in vitro assay conditions that may not fully replicate in vivo hepatic metabolism, potential incomplete characterization of intestinal metabolism and transporter involvement, and lack of prospective clinical studies in older adults to validate predicted exposure increases. The research advances understanding of CBD pharmacokinetics but should be considered hypothesis-generating rather than definitive for clinical practice. Future prospective pharmacokinetic studies in older adults are needed to confirm model predictions and establish evidence-based dosing recommendations for this vulnerable population.

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