As anyone who has worked in the pharmaceutical industry for awhile can tell you, there are many challenges, but one in particular keeps many of us up at night – the specter of drug-induced liver injury (DILI) lurking later in the drug development process. This can be a costly and time-consuming roadblock, derailing promising medications and delaying the arrival of treatments for patients in need.
The question, then, becomes: How early should we be thinking about DILI? The answer, unequivocally, is: From the very beginning.
Here’s why:
The Cost of Late-Stage DILI
Imagine pouring years of research and millions of dollars into a potential medication (the ballpark cost ranges for phase II and III studies can be $10-20M and $50-150M, respectively1,2), only to discover in Phase II or III trials that it causes liver damage. This scenario is devastating. Not only are resources wasted, but the delay in bringing a potentially life-saving drug to market can have immeasurable human consequences. Furthermore, volunteers and/or patients have been needlessly exposed to a potentially harmful substance.
A better scenario for all stakeholders is early detection of DILI risk, which can be done leveraging in vitro studies and the DILIsym software as soon as your candidate is synthesized. Check out our resource center for two relevant examples: killing a bad candidate prior to clinical studies and proactively assessing liver risk compared to competitor compounds early in development.
Opportunity Cost
The name of the game in therapeutic development comes down to blockbuster drugs. Most of the revenue generated by the pharma industry is generated off of a relatively small number of highly successful therapies, whereas many development programs fall by the wayside. For these highly successful drugs, a billion-dollar seller equates to at least $3M per day of potential revenue. Bottom line: you cannot afford to waste precious resources on candidates that could have been ruled out well in advance via non-clinical methods.
When you leverage modeling and simulation to predict DILI risk earlier in the drug development process, you can accelerate your time to market by up to 12 to 18 months, as well as avoid wasting precious time on unfit candidates that should be spent on your next blockbuster.
DILI Mechanisms Are Complex
DILI isn’t a one-size-fits-all phenomenon. Different drugs cause liver injury through various mechanisms. Once you understand the safety profile of a drug candidate, there is no guarantee that a similar compound in your portfolio has a similar likelihood of safety.
Our in silico models, such as DILIsym, can analyze a drug’s actions and potential interactions within the body, providing valuable insights into its hepatotoxic potential within the context of exposures that are relevant for therapeutic intervention. It also allows you to simulate a variety of dosing strategies to optimize for safety as well as highest efficacy—which is much less expensive than using traditional toxicology methods.
Minimization of Animal Use
The FDA Modernization Act3 has expedited an already prevailing sentiment that animal usage should be minimized where possible during the development of products for human use. And in an era of tightened budgets and skyrocketing costs of animal studies, it is prudent to use in silico methods when possible and appropriate.
The DILIsym software workflow includes in vitro studies and in silico simulations, none of which rely on animals while still providing valuable and clinically relevant insight into safety margins.
It’s all well and good to say that knowing about potential DILI risks earlier would be beneficial, but what solutions are actually available to enable earlier DILI predictions and avoidance of late-stage failures and wasted resources? The right solution for your program depends on the resources you have at your disposal.
Internal Modeling and Simulation Resources Available
If your organization has mechanistic modeling and simulation resources available to dedicate time to exposure and DILI predictions, a combination of software licenses to DILIsym (newest version – DSX) and GastroPlus (newest version – GPX) and training are available to equip your internal team to get started. Our team of experts at Simulations Plus can also guide you on the in vitro studies needed for DILI predictions, help facilitate connections with experimental service providers, or even contract the data collection for you via our white glove service. As your development programs evolve and your workload ebbs and flows, our team can also customize an internal/external plan to provide consulting services such as software / file setup, QC, and analysis as needed. We can flex as you flex to optimize your time allocations and success.
Minimal Modeling and Simulation Resources Available Internally
Part of a smaller startup or biotech where everyone wears ten hats? If so, our white glove consultancy service can lay out a comprehensive workflow for your team, customized for earlier drug development screening vs. late-stage regulatory analysis, to ensure your team can take advantage of these cutting-edge tools without a large pharma headcount.
The Future of Drug Development: Quantitative Methods
In conclusion, early DILI prediction is not just beneficial, it’s becoming increasingly essential in today’s competitive and cost-conscious pharmaceutical landscape, where the use of quantitative methods to expedite development is becoming mainstream and embraced by regulators.4 By embracing the use of DILIsym with GastroPlus PBPK modeling for small molecule candidates, companies can streamline drug development, reduce risks, and ultimately deliver safe and effective medications to patients faster. This not only benefits pharmaceutical companies but, more importantly, holds the potential to improve the lives of millions who suffer from unmet medical needs.
At Simulations Plus, we are committed to being at the forefront of drug development technology. We believe that by working together, pharmaceutical companies, researchers, and computational scientists like us can usher in a new era of safer and more efficient drug development, ultimately bringing the promise of better and more affordable health to all.
If you’re interested in support for evaluating DILI risk, let us know.
- Jamanetwork.com
- Sofpromed.com
- https://www.congress.gov/bill/117th-congress/senate-bill/5002
- https://www.fda.gov/drugs/drug-safety-and-availability/cder-establishes-new-quantitative-medicine-center-excellence