(M-120) Quantitative Systems Toxicology Modeling of Otenaproxesul Liver Enzyme Elevations Leads to Prediction of Liver Safety for Acute Otenaproxesul Dosing
Senior Principal Scientist Simulations Plus Raleigh, North Carolina, United States
Disclosure(s):
Jeff L. Woodhead, PhD: No financial relationships to disclose
Objectives: Otenaproxesul is a pain-reducing medicine consisting of naproxen bound to a 4-hydroxythiobenzamide moiety that releases the powerful antioxidant: hydrogen sulfide (H2S). This mechanism makes otenaproxesul less toxic to the gut tissue compared to naproxen alone. Liver enzyme elevations were observed in some chronic dosing clinical trials; these elevations occurred mostly after the cessation of dosing. Quantitative systems toxicology (QST) modeling using DILIsym® v8A was undertaken in order to explain the observed liver signals and predict acute dosing protocols that would be liver safe.
Methods: A PBPK model for several formulations of otenaproxesul, including a novel rapid-release formulation, was constructed in GastroPlus® 9.8. DILIsym v8A was modified to represent the scavenging of reactive oxygen species (ROS) by the H2S released by otenaproxesul. In vitro experiments describing the potential mechanism of drug-induced liver signals for both otenaproxesul and its main metabolite, M25 (naproxen), were used to create a representation of otenaproxesul in DILIsym v8A. The representation was validated against clinical liver function test data and was used to predict the likelihood of liver enzyme elevations in several proposed acute dosing protocols.
Results: Initial simulation results suggested that the post-treatment liver enzyme elevations were due to the replacement of endogenous antioxidant mechanisms with the drug-supplied H2S in certain individuals. In individuals with pre-existing capabilities or adaptation to elevated levels of ambient ROS, the influx of H2S would lead to a substantial decrease in ROS and, in time, to the cessation of the adaptive mechanisms (ie de-adaptation) that enabled hepatocytes to manage the elevated ambient ROS. Upon removal of the treatment, endogenous antioxidant mechanisms were slow to recover (ie re-adapt) while ambient ROS returned to pre-treatment levels, leading to liver injury. This hypothesis was able to explain all the post-treatment enzyme elevations observed in the clinic. The proposed acute dosing protocols were able to avoid full de-adaptation and thus were predicted to be liver-safe. Subsequent clinical experience validated the prediction of liver safety for one of the proposed acute dosing protocols.
Conclusions: DILIsym modeling was used to propose a plausible hypothesis for otenaproxesul-related liver enzyme elevations, to demonstrate that the hypothesis was able to explain clinical liver function test abnormalities, and to use these results to propose shifting the dosing strategy for otenaproxesul towards safer acute dosing protocols that were later validated clinically. This demonstrates that the lessons gleaned from QST modeling about the causes of liver injury can be used to de-risk future clinical development.
