News

DSSI and Otsuka Joint Publication – DILIsym used to identify Mechanisms of Tolvaptan Hepatotoxicity

Tolvaptan is a promising treatment for Autosomal Dominant Polycystic Kidney Disease (ADPKD), but was not approved by the FDA because some patients in the clinical trials developed liver injury. Starting in 2014, Otsuka sponsored the Tolvaptan Initiative, a multi-project, multi-disciplinary effort to 1) provide a mechanistic understanding of tolvaptan toxicity and 2) identify genetic and non‑genetic risk factors that could be used in the clinic to identify ADPKD patients at risk for tolvaptan‑induced liver injury.  DSSI was engaged by Otsuka to apply DILIsym® software to address this challenge. In vitro data on potential mechanisms of toxicity of parent tolvaptan and its major metabolites were obtained by BioEnergetics LLC and Dr. Kim Brouwer’s laboratory at the University of North Carolina (UNC) at Chapel Hill. Clinical data to perform PBPK modeling for tolvaptan and metabolites were provided to DSSI by Otsuka. DILIsym simulations using these data accurately reproduced the incidence of liver injury observed in the clinical trials, suggesting the mechanisms of toxicity identified in vitro could have predicted the liver safety liability of tolvaptan in the ADPKD population. Further analysis of the simulations led to the identification of pre‑treatment and on‑treatment blood tests that may be useful in the clinic to identify susceptible subjects before they develop liver injury. Together, the results provide a mechanistic back-drop for the observed liver signals and support ongoing efforts to identify and qualify biomarkers to manage the risk of liver injury in tolvaptan treated patients with ADPKD. In addition, this work builds on prior publications that support the use of DILIsym® in understanding, predicting and preventing drug-induced liver injury.

Researchers at Otsuka, BioEnergetics, UNC, and DSSI collaborated on a joint manuscript describing this research. The manuscript has been published by Toxicological Sciences and is available via open access:

https://www.ncbi.nlm.nih.gov/pubmed/27655350