A Physiologically-Based Pharmacokinetic Model for Cannabidiol in Healthy Adults, Hepatically-Impaired Adults, and ChildrenS

Cannabidiol (CBD) is available as a prescription oral drug that is indi-cated for the treatment of some types of epilepsy in children and adults. CBD is also available over-the-counter and is used to self-treat a variety of other ailments, including pain, anxiety, and insomnia. Ac-cordingly, CBD may be consumed with other medications, resulting in possible CBD-drug interactions. Such interactions can be predicted in healthy and hepatically-impaired (HI) adults and in children through physiologically based pharmacokinetic (PBPK) modeling and simula-tion. These PBPK models must be populated with CBD-specific param-eters, including the enzymes that metabolize CBD in adults. In vitro reaction phenotyping experiments showed that UDP-glucuronosyl-transferases (UGTs, 80%), particularly UGT2B7 (64%), were the major contributors to CBD metabolism in adult human liver microsomes. Among the cytochrome P450s (CYPs) tested, CYP2C19 (5.7%) and CYP3A (6.5%) were the major CYPs responsible for CBD metabolism. Using these and other physicochemical parameters, a CBD PBPK model was developed and validated for healthy adults. This model was then extended to predict CBD systemic exposure in HI adults and chil-dren. Our PBPK model successfully predicted CBD systemic exposure in both populations within 0.5-to 2-fold of the observed values. In con-clusion, we developed and validated a PBPK model to predict CBD sys-temic exposure in healthy and HI adults and children. This model can be used to predict CBD-drug or CBD-drug-disease interactions in these populations.