Assessing the Potential for Hepatotoxicity for Combination Therapy of Valproate (VPA) and CBDusing Quantitative Systems Toxicology (QST) DILIsym Correctly Predicts CBD ALT Elevations and Evaluates Interaction Mechanism(s)

Authors: Lakhani VV
Conference: AASLD
Keywords: ALT, DILIsym, gastroplus, hepatotoxicity, metabolites, QST
Software: DILIsym®, GastroPlus®
Division: Quantitative Systems Pharmacology (QSP)

Project Scenario and Goal

  • Epidiolex (highly purified CBD) is efficacious in treating seizures associated with Dravetsyndrome (DS), Lennox-Gastautsyndrome (LGS), and Tuberous Sclerosis Complex (TSC)
  • In the clinical trials of these patients, ALT elevations were seen in 21% of trial participants taking CBD with concomitant valproate (VPA) compared with 3% in participants not taking VPA [Epidiolexprescription info]
  • GOAL: To identify the mechanism(s) accounting for the higher incidence of ALT elevation observed during concomitant treatment with VPA and CBD by using a Quantitative Systems Toxicology (QST) model of hepatotoxicity (DILIsym®)
  • HYPOTHESIS: Increased incidence of ALT elevations was due to VPA and CBD (or metabolites of each) inhibiting mitochondrial respiration

By Vinal Lakhani

Presented at AASLD FDA DILI Conference April 20-21, 2021

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