Abstract
PurposeAutosomal-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.MethodsIn 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.ResultsNo 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.ConclusionsThese results demonstrate the potential for using QST methods to differentiate drugs in the same class for their potential to cause hepatotoxicity.
Highlights
Lixivaptan is a selective vasopressin V2 receptor antagonist that was initially developed for the treatment of hyponatremia [1] and is currently being repurposed for the treatment of autosomal-dominant polycystic kidney disease (ADPKD)
Considering the liver safety issues faced by tolvaptan, it is desirable to compare the potential for liver toxicity due to lixivaptan to that observed for tolvaptan in order to determine whether lixivaptan could become a safer treatment option for the treatment of ADPKD
The Physiologically-Based Pharmacokinetic (PBPK) modeling was successful in recapitulating the clinically observed plasma time courses of lixivaptan and its metabolites, as well as the likely liver-to-plasma ratio for the molecules based on rat mass balance studies and on data collected for this work
Summary
Lixivaptan is a selective vasopressin V2 receptor antagonist that was initially developed for the treatment of hyponatremia [1] and is currently being repurposed for the treatment of autosomal-dominant polycystic kidney disease (ADPKD). Acute liver failure requiring liver transplantation has been reported in the post-marketing experience with tolvaptan, and frequent liver chemistry monitoring is recommended for patients taking tolvaptan for ADPKD [4]. Despite these liver safety concerns, the unmet need for ADPKD treatment has supported tolvaptan’s approval in multiple countries, including the US. Quantitative systems toxicology (QST) modeling combines knowledge about the effects of a drug in in vitro systems with knowledge about physiology to describe a drug’s potential for toxicity. DILIsym®, a QST platform model of drug-induced liver injury, has been successful in describing the differences between three
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