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

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.

A mechanistic model of drug-induced liver injury AIDS the interpretation of elevated liver transaminase levels in a phase I clinical trial.

Entolimod (CBLB502) is a Toll-like receptor 5 agonist in development as a single-dose countermeasure against total body irradiation. Efficacy can be assessed from animal studies, but the "Animal Rule" does not apply to safety assessment. Marked elevations of serum aminotransferases (exceeding 1,000 IU/l) were observed in some human subjects receiving Entolimod in a safety study, threatening its continued development. The percentage of total hepatocytes undergoing necrosis in these subjects was estimated using a mechanistic, multiscale, mathematical model (DILIsym). The simulations suggested that no subject in the safety study experienced more than a modest loss of hepatocytes (<5%), which was comparable to estimates from a study of healthy volunteers receiving treatment with heparins. The predicted hepatocyte loss with Entolimod was lower than that required to cause liver dysfunction or that is routinely excised from volunteers donating for autologous liver transplantation and did not likely represent a serious health risk.