Comparison of the Hepatotoxic Potential of Two Treatments for Autosomal-Dominant Polycystic Kidney DiseaseUsing Quantitative Systems Toxicology Modeling

Authors: Woodhead JL, Pellegrini L, Shoda LKM, Howell BA
Publication: Pharm Res
Keywords: autosomal-dominant polycystic kidney disease, bile acids, celebrate qsp, DILIsym, liver injury, mitochondria, Quantitative Systems Toxicology (QST)
Software: DILIsym®
Division: Quantitative Systems Pharmacology (QSP)

Abstract

Purpose
Autosomal-dominant polycystic kidney disease (ADPKD) is an orphan disease with few current treatment options. The vasopressin V2 receptor antagonist tolvaptan is approved in multiple countries for the treatment of ADPKD, however its use is associated with clinically significant drug-induced liver injury.

Methods
In prior studies, the potential for hepatotoxicity of tolvaptan was correctly predicted using DILIsym®, a quantitative systems toxicology (QST) mathematical model of drug-induced liver injury. In the current study, we evaluated lixivaptan, another proposed ADPKD treatment and vasopressin V2 receptor antagonist, using DILIsym®. Simulations were conducted that assessed the potential for lixivaptan and its three main metabolites to cause hepatotoxicity due to three injury mechanisms: bile acid accumulation, mitochondrial dysfunction, and oxidative stress generation. Results of these simulations were compared to previously published DILIsym results for tolvaptan.

Results
No ALT elevations were predicted to occur at the proposed clinical dose for lixivaptan, in contrast to previously published simulation results for tolvaptan. As such, lixivaptan was predicted to have a markedly lower risk of hepatotoxicity compared to tolvaptan with respect to the hepatotoxicity mechanisms represented in DILIsym.

Conclusions
These results demonstrate the potential for using QST methods to differentiate drugs in the same class for their potential to cause hepatotoxicity, particularly when patients will be given one molecule versus the other one. Note that lixivaptan clinical development has subsequently been halted based on a liver safety event in the ALERT clinical trial.  This trial only enrolled patients who had terminated treatment with tolvaptan due to liver toxicity.  Apparently, all but this patient was able to be safely converted to tolvaptan.  The DILIsym prediction that the liver safety of  lixivaptan is much greater than tolvaptan has not been disproven and is actually supported by the ALERT trial.   For additional discussion see Dr. Watkins’ blog post.

By Jeff Woodhead, Lisl Shoda,  Brett Howell