Assessing the Potential for Hepatotoxicity for Combination Therapy of Valproate (VPA) and Cannabidiol (CBD) using Quantitative Systems Toxicology (QST)

Authors: Lakhani VV, Generaux GT, Howell BA, Watkins PB, Longo DM
Conference: AAPS
Keywords: ALT elevations, CBD, Dravet syndrome, Epidiolex, hepatotoxicity, Lennox-Gastaut syndrome, valproate
Software: DILIsym®
Division: Quantitative Systems Pharmacology (QSP)

Purpose ​

Highly purified cannabidiol (CBD) (approved as Epidiolex in the US) is efficacious in treating seizures associated with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and Tuberous Sclerosis Complex (TSC).  In Epidiolex clinical trials, frequent and dose-dependent elevations in serum alanine aminotransferase (ALT) were observed. In Epidiolex-treated patients with LGS, DS, or TSC (10 or 20 mg/kg/day dosages), the incidence of ALT elevations >3x the upper limit of normal (ULN) was 21% in participants taking CBD with concomitant valproate (VPA) compared with 3% in participants not taking VPA; this interaction was not pharmacokinetic. Here, we aimed to identify the mechanism(s) accounting for the higher incidence of ALT elevation observed in individuals treated with VPA and CBD.

By Vinal V Lakhani, Grant Generaux, Brett A Howell, Paul B Watkins, Diane M Longo

​Presented at American Association of Pharmaceutical Scientists (AAPS) PharmSci 360, October 17-20, 2021