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

Pharm Res. 2020 Jan 6;37(2):24. doi: 10.1007/s11095-019-2726-0.

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.

Keywords: Liver injury; autosomal-dominant polycystic kidney disease; bile acids; mitochondria; quantitative systems toxicology.

MeSH terms

  • Benzamides / adverse effects*
  • Benzamides / pharmacology
  • Chemical and Drug Induced Liver Injury / etiology*
  • Drug-Related Side Effects and Adverse Reactions / etiology*
  • Humans
  • Models, Theoretical
  • Polycystic Kidney, Autosomal Dominant / drug therapy*
  • Pyrroles / adverse effects*
  • Pyrroles / pharmacology
  • Tolvaptan / adverse effects*
  • Tolvaptan / pharmacology

Substances

  • Benzamides
  • Pyrroles
  • Tolvaptan
  • lixivaptan