Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity

Cannabidiol (CBD) is a pharmacologically active metabolite of cannabis that is US Food and Drug Administration approved to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children aged 1 year and older. During clinical trials, CBD caused dose-dependent hepatocellular toxicity at therapeutic doses. The risk for toxicity was increased in patients taking valproate, another hepatotoxic antiepileptic drug, through an unknown mechanism. With the growing popularity of CBD in the consumer market, an improved understanding of the safety risks associated with CBD is needed to ensure public health. This review details current efforts to describe CBD pharmacokinetics and mechanisms of hepatotoxicity using both pharmacokinetic models and in vitro models of the liver. In addition, current evidence and knowledge gaps related to intracellular mechanisms of CBD-induced hepatotoxicity are described. The authors propose future directions that combine systems-based models with markers of CBD-induced hepatotoxicity to understand how CBD pharmacokinetics may influence the adverse effect profile and risk of liver injury for those taking CBD. SIGNIFICANCE STATEMENT: This review describes current pharmacokinetic modeling approaches to capture the metabolic clearance and safety profile of cannabidiol (CBD). CBD is an increasingly popular natural product and US Food and Drug Administration-approved antiepileptic drug known to cause clinically significant enzyme-mediated drug interactions and hepatotoxicity at therapeutic doses. CBD metabolism, pharmacokinetics, and putative mechanisms of CBD-induced liver injury are summarized from available preclinical data to inform future modeling efforts for understanding CBD toxicity.