By Tim Moeller
In today’s competitive economic climate, the financial implications of being the first to file a promising new drug cannot be underestimated. While hepatocytes are used successfully by pharmaceutical scientists to compress the overall discovery timeline, a reliance on fresh hepatocytes can present a number of challenges. These typically include lack of donor availability, difficulty matching profiles, unknown enzymatic activities, inability to repeat experiments from the same donor, and scheduling issues — all of which can cause significant project delays and result in overall bottom-line inefficiencies.
Leading researchers and drug manufacturers have been able to overcome these uncertainties by leveraging the advantages of cryo-plateable hepatocytes, as follows.
Reduced Time Delays And Data Variability: As drug manufacturers strive to bring new products to market, time and predictability throughout the R&D process are essential. Even in the preclinical phase, scheduling delays may slow the testing of early investigational compounds, costing the manufacturer lost time and money. In many cases, freshly isolated hepatocytes may not be readily available due to a reliance on fresh liver donations and can also lead to overtime work as staff must remain on call for a liver. While resects from biopsies may improve availability, they are potentially dangerous as they cannot, by law, include full serology reporting. In contrast, fully characterized cryopreserved hepatocytes can be immediately procured in large inventories and stored at the laboratory, controlling the scheduling of studies and accelerating time to market. Standard induction studies, as an example, typically may be completed 50% faster using cryo-plateable hepatocytes.
Improved Efficiency: Cryopreserved hepatocytes may be precharacterized for enzyme activities, genotypes, and for applications like induction or transport, representing another major advantage over fresh products. In fact, cryopreserved products may be obtained to meet specific donor requirements while maintaining high levels of viability, confluence, or activity, allowing the researcher to choose the right lot for their application. Large inventories and a minimum five-year shelf life allow researchers to repeat tests at future dates with no difference in product performance. Likewise, research being conducted at multiple sites can draw from the same product lot for consistent, simultaneous studies worldwide.
Fewer Restrictions: The limitations of freshly isolated hepatocytes for studies like induction severely restrict the researcher’s choices for timing, demographics, and retesting. Cryopreservation of these cells permits expanded investigation while retaining clinically significant activity. By removing constraints associated with tissue availability, cryopreservation allows for further testing of activity and genomic characterizations, retesting from the same donor, and scheduling assays at the researcher’s discretion, plus it more fully utilizes precious donated resources.
FDA Equivalency: The use of cryo-plateable hepatocytes is recognized as equivalent to using freshly isolated hepatocytes. Acknowledging this trend, the FDA drafted a Guidance for Industry in 2006 advising that cryopreserved tools are a viable and acceptable alternative to fresh research products, especially in metabolism, toxicity, and drug-drug interaction testing. Several large pharmaceutical companies have adopted cryopreserved hepatocytes as their primary model for stability, transport, and induction studies as evidenced in peer-reviewed literature. As researchers recognize the benefits of cryopreserved hepatocytes for traditional ADME-Tox (absorption, distribution, metabolism, excretion, and toxicology) studies, a broader range of new applications are being adopted, including high-throughput screening (HTS) and high-content screening (HCS).
In summary, by harnessing the benefits of freshly isolated plateability and the efficiencies of cryopreservation, life sciences companies no longer have to compromise their safety, schedule, or productivity. Given their many advantages, the benefits of using cryopreserved hepatocytes, in suspension or plated, outweigh those of fresh products and should be strongly considered.
Timothy A. Moeller is a scientific advisor at Celsis In Vitro Technologies (IVT), a world provider of specialized in vitro products for the study of metabolism, drug-drug interactions, and toxicity in drug discovery and development. He has been with Celsis for six years in research and development, CRO, and product operations. He can be reached at IVTinfo@celsis.com.