Elevated ALT levels during clinical trials led researchers to use quantitative systems toxicology (QST) software to better understand potential underlying mechanisms

Simulations Plus, Inc. (Nasdaq: SLP), a leading provider of modeling and simulation software and services for pharmaceutical safety and efficacy, today shared an article published in the July 2023 issue of Clinical Pharmacology & Therapeutics in which researchers explained how they used the DILIsym^® software platform to explore why patients receiving treatment with valproate (VPA) are more sensitive to elevations in liver chemistries due to cannabidiol (CBD).

DILIsym is a quantitative systems toxicology (QST) software platform designed to be used during drug development for predicting drug-induced liver injury (DILI) and can provide insight into the mechanisms responsible for DILI responses through the development process.

CBD is an FDA-approved treatment for seizures in patients diagnosed with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. During the pre-approval clinical trials, treatment with CBD was occasionally associated with elevation in blood levels of ALT, a marker of liver injury, but this was much more common in patients already receiving treatment with VPA for seizures. To identify potential underlying mechanisms, researchers used DILIsym to predict ALT levels in simulated populations that were treated with CBD alone, treated with VPA alone, and then treated with VPA before they were treated with CBD.

“Since so many people are now taking CBD in over-the-counter preparations, it was important to understand this effect of VPA to determine whether there are other drug treatments or patient risk factors that might increase risk for liver injury due to CBD,” said Dr. Paul Watkins, senior author on the manuscript and professor at The University of North Carolina at Chapel Hill.

DILIsym predicted dose-dependent ALT elevations for CBD treatment and ALT elevations for VPA treatment when each was given alone, but the combined VPA and CBD treatment protocol mimicking the clinical trials did not increase the incidence of ALT elevations relative to CBD treatment on its own.

Watkins continued, “This suggests that VPA-CBD interaction does not involve the major mechanisms underlying liver injury due to drugs, which are incorporated into DILIsym. This effect of VPA might be specific to this drug, reducing concern that there may be common risk factors.”

“DILIsym provides critical information for researchers in the pharmaceutical development space faced with decisions regarding the safety of their drugs and combined therapies,” said Dr. Brett Howell, President of the DILIsym Services division of Simulations Plus. “We are committed to supporting our clients in identifying and mitigating risks in the drug design and development process, and ultimately to the patients who are awaiting improved treatments.”

The full article can be found here.

Researchers can learn more about DILIsym or other modeling and simulation software on the Simulations Plus website.

About Simulations Plus

Serving clients worldwide for more than 25 years, Simulations Plus is a leading provider in the biosimulation market providing software and consulting services supporting drug discovery, development, research, and regulatory submissions. We offer solutions that bridge artificial intelligence (AI)/machine learning, physiologically based pharmacokinetics, quantitative systems pharmacology/toxicology, and population PK/PD modeling approaches. Our technology is licensed and applied by major pharmaceutical, biotechnology, and regulatory agencies worldwide. For more information, visit our website at www.simulations-plus.com. Follow us on LinkedIn | Twitter | YouTube.

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