Prospective Liver Safety Comparison of Two Treatments for Autosomal-Dominant Polycystic Kidney Disease (ADPKD) Using Quantitative Systems Toxicology Modeling
Objectives: Lixivaptan, a vasopressin-2 receptor antagonist, is in development for the treatment of ADPKD, an orphan disease with high unmet medical need. The main objective of this research was to prospectively compare the potential for lixivaptan to cause liver toxicity to a comparator drug in the same class, tolvaptan, which has produced off-target liver signals in clinical trials1.
Methods: In vitro data relating to reactive oxygen species formation, mitochondrial toxicity, and bile acid transporter inhibition for lixivaptan and its metabolites were collected. Using these data, lixivaptan and its metabolites were represented in DILIsym, a platform QST model of drug-induced liver injury. Lixivaptan PBPK was also represented within DILIsym, incorporating clinical trial PK data. Proposed ADPKD treatment dosing regimens were simulated and the predicted potential for liver enzyme elevations was compared to that previously determined for tolvaptan in DILIsym2.
Results: Lixivaptan was not predicted to cause liver enzyme elevations in a simulated human population which includes variability in toxicity susceptibility and pharmacokinetics, while tolvaptan was correctly predicted to cause rare liver enzyme elevations in a similar population (Table 1). Mechanistic simulations at supratherapeutic doses suggest that potential liver toxicity mechanisms for lixivaptan are different from those identified for tolvaptan. Conclusions: Lixivaptan was predicted to be safer than tolvaptan with respect to the liver toxicity mechanisms represented in DILIsym. Quantitative and qualitative differences were identified between the two drugs. These findings pave the way for confirmatory clinical trials with lixivaptan in ADPKD.
Eighth American Conference on Pharmacometrics, October 15-18, 2017, Ft. Lauderdale, FL
By Jeffery Woodhead, Scott Q Siler, Lisl Shoda, Paul B Watkins, Brett A Howell