Assessing Liver Effects of Cannabidiol and Valproate Alone and in Combination Using Quantitative Systems Toxicology

Abstract

In clinical trials of cannabidiol (CBD) for the treatment of seizures in patients with Dravet syndrome, Lennox–Gastaut syndrome, and tuberous sclerosis complex, elevations in serum alanine aminotransferase (ALT) > 3× the upper limit of normal were observed in some patents, but the incidence was much greater in patients who were receiving treatment with valproate (VPA) before starting CBD. To explore potential mechanisms underlying this interaction, we used DILIsym, a quantitative systems toxicology model, to predict ALT elevations in a simulated human population treated with CBD alone, VPA alone, and when CBD dosing was starting during treatment with VPA. We gathered in vitro data assessing the potential for CBD, the two major CBD metabolites, and VPA to cause hepatotoxicity via inhibition of bile acid transporters, mitochondrial dysfunction, and production of reactive oxygen species (ROS). Physiologically‐based pharmacokinetic models for CBD and VPA were used to predict liver exposure. DILIsym simulations predicted dose‐dependent ALT elevations from CBD treatment and this was predominantly driven by ROS production from the parent molecule. DILIsym also predicted VPA treatment to cause ALT elevations which were transient when mitochondrial biogenesis was incorporated into the model. Contrary to the clinical experience, simulation of 2 weeks treatment with VPA prior to introduction of CBD treatment did not predict an increase of the incidence of ALT elevations relative to CBD treatment alone. We conclude that the marked increased incidence of CBD‐associated ALT elevations in patients already receiving VPA is unlikely to involve the three major mechanisms of direct hepatotoxicity.

Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity

“…Finally, despite the fact that patients taking CBD are commonly co-prescribed VPA for seizure management (Devinsky et al, 2017(Devinsky et al, , 2018, very few studies have sought to examine mechanisms of the hepatotoxic DDI observed between CBD and VPA in clinical trials. (Lakhani et al, 2023). The resulting simulations suggested that CBD-induced hepatotoxicity is associated with generation of ROS for patients taking VPA who began CBD therapy (Lakhani et al, 2023).…”

Clinical Pharmacology of Cannabinoid Therapeutics: Drug Interactions and Side Effects

“…In the current issue of Clinical Pharmacology & Therapeutics ( CPT ), Lakhani et al 15 . describe an elegant quantitative systems toxicology approach to further investigate the clinical observed liver toxicity of CBD when co‐administered with VPA ( Figure ).…”

“…To investigate the possible mechanisms, Lakhani et al 15 . used the DILIsym software, a tool developed jointly among academia, industry, and the US Food and Drug Administration (FDA).…”

“…In the current issue of Clinical Pharmacology & Therapeutics (CPT), Lakhani et al 15 describe an elegant quantitative systems toxicology approach to further investigate the clinical observed liver toxicity of CBD when co-administered with VPA (Figure 1). The background of this study was the observation of a substantial increase in serum ALT when CBD is administered in addition to the anticonvulsant VPA.…”

“…To investigate the possible mechanisms, Lakhani et al 15 used the DILIsym software, a tool developed jointly among academia, industry, and the US Food and Drug Administration (FDA). As a starting point, a physiologicallybased pharmacokinetic (PBPK) model was applied to simulate exposure of 1,500 mg b.i.d.…”