LB-017 - ASSESSING THE IMPACT OF AGE ON CANNABINOID DISPOSITION

L. Qian¹, M. Paine², Z. Zhou¹; ¹York College, City University of New York, New York, NY, United States, ²Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, United States.

Background: Cannabis use among older adults continues to increase, yet an understanding of the effects of age on the disposition of key phytoconstituents, namely the cannabinoids cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (THC), remains lacking. CBD is metabolized primarily by cytochrome P450 (CYP) 2C19, CYP3A, and UDP-glucuronosyltransferases (UGTs), whereas THC is metabolized primarily by CYP2C9 and CYP3A. However, the reported relative contributions of these enzymes are variable. Collectively, the aims of this work were to 1) determine the fractional contributions of the relevant enzymes to CBD and THC metabolism by verifying physiologically based pharmacokinetic (PBPK) models with drug-drug interaction (DDI) studies and 2) assess the impact of age on cannabinoid disposition by applying the PBPK models.

Methods: Our previously verified PBPK models for CBD and THC using Simcyp™ were applied to predict the systemic exposure to each cannabinoid in the absence and presence of select precipitant drugs. Specifically, we assessed the effects of rifampicin (CYP3A/2C inducer), ketoconazole (CYP3A inhibitor), and omeprazole (CYP2C19 inhibitor) on CBD and THC exposure, as well as the effects of stiripentol (CYP2C19 inhibitor) and valproic acid (UGT/CYP2C9 inhibitor) on CBD exposure. After verifying the fractional enzyme contributions to cannabinoid metabolism, the models were extrapolated to predict cannabinoid exposure in older adults using the “geriatric population (ages 65-98)” module within Simcyp™.

Results: The models well-captured AUC0-t and Cmax of CBD and THC, with predicted values ranging from 0.69- to 1.94-fold of observed values from five clinical studies (Fig. 1A, 1B). Predicted AUC0-t ratios (AUC0-t of cannabinoid in the presence to absence of precipitant) were within 0.68- to 1.48-fold of observed ratios (Fig. 1C). Systemic exposure to both CBD and THC after a 10-mg oral dose was ~1.45-fold higher in older compared to young adults (Fig. 1D).

Conclusion: Our PBPK models predicted an ~45% higher systemic exposure to CBD and THC in older compared to younger adults, suggesting that age-related changes may require dose adjustment for each cannabinoid in older populations. Further comprehensive studies are needed to confirm this observation.