DILIsym® Context of Use
DILIsym® is designed to be used during drug development to provide enhanced understanding of the DILI hazard posed by individual molecules, and to provide deeper insight into the mechanisms responsible for observed DILI responses at various stages of the development process. In the short term, it is envisaged that this information will be integrated with other key, nonclinical safety data, and will form a part of the weight of evidence for safety assessment prior to undertaking nonclinical in vivo regulatory safety studies and prior to progression of drug candidate compounds into man. In the longer term, it is envisaged that use of DILIsym® will improve human risk assessment and provide enhanced opportunities for customized clinical safety monitoring during all phases of clinical development.
Areas of Application within Drug Development
DILIsym® will integrate a range of mechanistically relevant in silico, in vitro and in vivo data, in order to provide a virtual DILI hazard profile for an individual molecule. This profile will be used to aid in selection of drug candidates that have reduced propensity to cause DILI at key stages of drug development, such as:
- During drug discovery, where the virtual DILI hazard profile will enable a better understanding of the relative DILI hazards posed by individual compounds within pharmacologically and structurally related series and between compound series; the goal is to inform and support selection of compounds and chemical series for progression through discovery that have the most favorable balance between pharmacological activity, DMPK, physical chemistry and other key properties, and low propensity to cause DILI
- During compound progression into development, where the virtual DILI hazard profile will inform and enhance selection of compounds for in vivo safety evaluation in nonclinical test species; DILIsym® will then help ensure the design of the in vivo safety evaluation studies is as efficient and effective as possible given the information known about any possible DILI modalities
- During nonclinical to clinical translation, where in vivo nonclinical safety data have been obtained and the virtual DILI hazard profile will aid in interpretation of the relevance to man posed by any DILI signals observed in vivo in the nonclinical test species; DILIsym® will also help in understanding species differences among pre-clinical models, and aid in better defining the modes of action responsible for any observed differences in DILI response
- During clinical trials, where the virtual DILI hazard profile will also enable identification and selection of nonstandard, mechanistically relevant DILI safety biomarkers and marker panels; such markers and marker panels can be used to monitor early functional events that ultimately may result in DILI during clinical trials and so enable improved personalized healthcare
Application Examples with DILIsym®
DILIsym® is currently under development through the DILI-sim Initiative. Significant advances to the model are expected through the end of 2017 and beyond. DILIsym® version 4B has been distributed to DILI-sim members. In addition, the model has been used to address a number of important applications related to DILI. Additional case studies can be viewed at the DILIsym Services website, www.DILIsymServices.com. A subset of early example use cases include:
Predicting the severity of liver injury from clinical biomarker data - Entolimod (CBLB502) is a toll-like receptor 5 (TLR5) agonist in development as a single dose countermeasure against total body irradiation. Efficacy could 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 percent of total hepatocytes undergoing necrosis in these subjects was estimated using DILIsym®. This was accomplished through a two-phase process. Initially, DILIsym® was optimized to produce the liver enzyme profiles observed in healthy volunteers administered Entolimod. Second, the underlying level of hepatocyte loss predicted by the model to give such profiles was assessed for its relevance to the safety of the healthy volunteers. 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.
In vitro to In vivo Extrapolation – In vitro data for the reactive metabolite producer methapyrilene was utilized to validate the DILIsym® software as predictive when translating in vitro data to in vivo predictions. With inclusion of variability in the underlying biology, all simulated mice and humans were predicted to be tolerant to the drug, while simulated rats displayed a wide range of response, including toxicity. These findings were in agreement with published data and reports. Moreover, the model allowed identification of the biological parameters in the rat that potentially underlie susceptibility to the toxicity of the drug. This demonstration of in vitro to in vivo extrapolation (IVIVE) shows the power for utilizing DILIsym® within drug discovery and compound progression.
Examining Hy's Law - Hy’s Law was examined, which specifies liver injury concerns in subjects with simultaneous elevations of ALT exceeding three times the upper limit of normal (ULN) and of bilirubin exceeding twice the ULN. The results suggested a possible link between ATP depletion in hepatocytes and subsequent bilirubin elevations. This example highlights the ability of DILIsym® to aid in identifying mechanistic links to clinical biomarkers.
Analyzing Clinical Paradigms - N-acetyl cysteine (NAC) is the standard therapy for acetaminophen (APAP) overdose, but there are differences in the route of administration used as well as the duration of treatment. DILIsym® results suggested that the oral NAC protocol may be the better treatment option than the IV protocol (assuming the same patient, APAP dose, and time of admission across the protocols). Furthermore, the amount of NAC given was higher with the oral protocol, and the IV protocol could be improved upon simply by giving bolus IV doses and matching the mass given orally. This example illustrates how DILIsym® may be used to compare clinical protocols under multiple scenarios (i.e., length of delay, treatment duration), understand the molecular basis of the predicted efficacy, and identify protocols that improve clinical results. Simulation results can then be used to help design confirmatory clinical studies.