The results of preclinical safety studies are crucial components in regulatory filing of a New Chemical Entity (NCE). A pharmaceutical company that had identified a pharmacological candidate for a significant unmet clinical need turned to an experienced team to partner with them in these development studies. The client needed to satisfy regulatory demands for their NCE to aggressive timelines and looked to Aptuit to robustly demonstrate the safety margin of the compound from its intended therapeutic dose. The pharmaceutical company had confidence that Aptuit could conduct a large number of animal-based studies and integrate the data into a single comprehensive program. Multiple preclinical areas were involved in the project including toxicology, bioanalysis, safety pharmacology and Drug Metabolism and Pharmacokinetics (DMPK).

The flexible scheduling of studies in the program involving rat and primate as species, had a positive impact on the overall project enhanced by an effective chain of communications. These properties enabled the team to not only troubleshoot problems as they occurred but identify potential issues and mitigate them. An unexpected finding did emerge as data were produced. Aptuit uncovered cardiac toxicity when the compound was administered to rats but paradoxically, found no cardiac toxicity in the studies performed on the higher species, primate. The emerging focus team, comprised of client and Aptuit scientists, not only defined the consequent regulatory questions that would develop, but also defined the studies that would be required to answer them. Neither the client nor Aptuit in isolation could achieve the quick turn around of these studies to meet the expected deadline. Working together, science-based evidence of a species specific effect was achieved in timing that would not have been achievable otherwise.

The Challenge

Aptuit was asked to conduct an extended package of preclinical studies within a short time frame. As the critical studies are dependent on the results of earlier work in the package (for example, initiation of the 28 day toxicology studies are dependent on the completion of bioanalytical method development, dose range finding, etc.) not only scheduling, but adherence to the schedule was the major risk to achievement of the overall aim, and on time filing to the regulator. As expected with a large program with many “moving” parts, there were many logistical issues in the scheduling. A careful plan for ongoing communications as the project developed was essential in troubleshooting problems as they might arise.

The Aptuit Solution

Aptuit’s extensive and varied experience in designing and conducting Comprehensive Preclinical Development Programs led to a schedule that effectively allowed for detecting problems through an efficient and comprehensive communications network. Aptuit’s Project Manager led the program, driving the multiple procedures to adhere to the schedule and meet projected time lines. Reporting methods and compliance were set at very high standards so that throughout the project’s duration, the client and Aptuit were able to work together as true partners.

Scientific interpretation during the drug development process

The production of data and reports on time and in full is crucial to maintaining the progress of an integrated drug development program. However, it is the engagement of the scientists in interpreting the findings, and understanding and communicating the impact to the overall program that ensures this process is dynamic and flexible as requirements to meet the final goal develop.

Histopathology expertise is a crucial element in toxicology studies

Robust and efficient histopathology expertise are essential to any successful package. Clarity and confidence in any findings facilitate the consequent decision process and assist in minimizing any delay they may produce. Pictured below are steps in histopathology slide staining of tissues.

Reliance on an intense schedule

The inter-reliance and co-dependence of a high number of individual studies are shown here. Analytical and Bioanalytical support all conducted within the same site underpin all of the key Safety Studies

• 28-day Toxicology
• Genotoxicology
• Safety Pharmacology
• In-Vivo Metabolism ADME

Focus on reporting dates and delivery to these, in some cases through acceleration of the process, is a key element to partnering with the client to achieve the final goal: regulatory submission.

Conclusion

The decision to work with Aptuit was based on the pharmaceutical company’s vast experience in the span of preclinical services, with particular interest in Aptuit’s proven ability to conduct and analyze a package of preclinical studies within an expeditious timeframe. Aptuit not only integrated the results of multiple tests reporting the species specific cardiac toxicity but, as a result of our substantial experience, Aptuit was able to work collaboratively with the client to identify and enact a new path to achieve the shared goal of IND submission. The client recognized Aptuit’s comprehensive range of services, many located all at one site with others accessible to scientists located at other global sites, was an important factor in ongoing group discussions among the many scientific professionals involved in the project.

Throughout the process, the pharmaceutical company and Aptuit shared the data, uncovering issues and co-managing them. Preclinical professionals, part of Aptuit’s Pharmaceutical Development and Manufacturing group, were readily accessible to the client. It was Aptuit’s substantial experience combined with collaborative input from scientists across the network that advanced the client’s pursuit of a viable compound that could withstand the technical scrutiny that precedes the initiation of a clinical program. At present, additional, new work with the client is under discussion, including long term toxicology, clinical bioanalysis, Oral and Phase IV clinical manufacturing and drug product stability. At Aptuit, it’s all about the science.