Key Challenges in Preclinical DILI Assessment
Drug-induced liver injury (DILI) remains a significant challenge in the development of safe and effective pharmaceuticals (1). The complexity of DILI assessment in the preclinical phase is compounded by the need for solutions that balance cost, throughput, and turnaround time without compromising sensitivity, specificity, reproducibility, and robustness. This blog delves into the trade-offs between complex, microfluidic DILI assessment methods and more scalable, robust solutions, mature enough for industrial application.
The High Cost of Complexity: Microfluidic Organ-on-Chip Systems
Microfluidic organ-on-chip (OoC) systems represent a significant advancement in mimicking human physiology for drug testing. These systems offer dynamic flow and mechanical forces that aim at closely replicating the in vivo environment. However, the sophistication of OoC systems comes with notable drawbacks:
High complexity and cost
The design and operation of OoC solutions are inherently complex, requiring specialized equipment and expertise. This complexity translates into significantly higher costs, up to 100 times more than alternative methods, making it a less viable option for routine DILI assessment across the drug development spectrum.
Increased test substance requirements
Organ-on-chip systems often necessitate larger quantities of test substances to maintain the dynamic flow conditions, posing challenges for safety screening, especially in early safety tiers where compound availability may be limited.
Extended turnaround times
The intricate setup and operation of OoC systems result in longer preparation and analysis times, doubling the turnaround time for data delivery compared to more streamlined approaches. This delay can impede the rapid decision-making process critical in drug development.
Use of large amounts of primary hepatocytes
The often-mesoscopic nature of organ-on-chips requires the use of large amounts of primary hepatocytes for DILI assessment, typically between 100,000 and 600,000 cells per device (and therefore, data points). This leads not only to a high cell consumption, it also requires frequent donor changes – including lot selection and validation.
The Scalable Advantage: 3D Liver Spheroids
In contrast, scalable 3D in vitro solutions like InSphero's 3D InSight™ DILI Testing platforms or re-aggregated liver spheroids in ULA microplates offer a compelling balance of physiological relevance and operational efficiency. These platforms harness the power of 3D cell-based assays to create liver models that accurately reflect human liver tissue architecture and function, without the operational complexity of OoC systems. The benefits resonate with a routine use to replace 2D sandwich cultures for this application:
Equivalent or superior sensitivity and specificity
InSphero's 3D models are engineered to detect DILI with high sensitivity and specificity, rivaling the performance of complex OoC systems. This ensures reliable identification of potential liver toxicities early in the drug development process but also includes late-stage mechanistic or patient-specific investigations.
Enhanced reproducibility and robustness
The standardized production and use of 3D liver spheroids minimize variability, leading to more consistent and robust data. This reproducibility is essential for the confident progression of drug candidates.
Cost-effectiveness
By simplifying the experimental setup and reducing the need for large quantities of test substances, InSphero's platforms offer a cost-efficient alternative for comprehensive DILI assessment, providing economic advantages without sacrificing data quality.
Faster turnaround time
The streamlined workflow of the 3D InSight™ platforms, both as services or products for in-house use, facilitates quicker data generation, enabling more agile decision-making and accelerating the drug development timeline.
Finding the Right Balance in DILI Assessment: Complexity, Cost and Scalability
As the pharmaceutical industry seeks to optimize the balance between technological sophistication and practical application in DILI assessment, the choice between complex microfluidic organ-on-chip systems and scalable 3D solutions becomes pivotal. InSphero's 3D InSight™ DILI Testing platforms emerge as a strategic choice, offering a blend of physiological relevance, operational simplicity, cost-efficiency, and speed. These scalable solutions not only meet but often exceed the capabilities of more complex systems, marking a significant step forward in enhancing drug safety assessments. In the quest for safer, more effective therapeutics, embracing scalable, efficient technologies is not merely an option—it is imperative.
References
- FDA's Predictive Toxicology Roadmap - https://www.fda.gov
