Considerations for Successful In Vivo IND-Enabling Work

This blog post was written by Meaghan Loy, MS, ALAT our Senior Category Director of In Vivo and GLP Services here at Scientist.com. Meaghan has over 11 years of combined experience in laboratory research, pre-clinical studies and scientific marketplaces to create and execute strategies that advance the sourcing of in vivo, GLP and IND-Enabling studies.

Embarking on the journey of IND-enabling work requires meticulous planning and attention to detail. Among the numerous challenges faced during this process, ensuring proper preparation of compounds for in vivo use stands out as a critical factor. In my experience, I have encountered pitfalls related to formulation that not only consumed valuable time but also had cascading effects on various downstream activities. Here, I’ll share insights gained from these experiences, offering practical tips to streamline the formulation process and enhance overall efficiency.

Identifying Formulation Challenges: A Common Hurdle

One recurring issue observed in the vivarium pertains to inadequately prepared compounds for in vivo use. Difficulties in achieving proper formulation, including issues like chunkiness, were noted. The use of DMSO as an excipient presented additional hurdles due to its potential unintended side-effects and unclear safety profile for human administration.

Tip 1: Formulate with the end in mind
Formulating compounds with the end goal in mind is crucial. Prior to the in vivo stage, thorough consideration of potential unintended side-effects, especially with excipients like DMSO, is essential. Opt for alternative excipients aligning with both animal and human safety considerations to avoid last-minute obstacles and meet stringent regulatory expectations.

Tip 2: Conduct pre-formulation assessments
Mitigate the risk of encountering formulation challenges by conducting pre-formulation assessments early in the drug development process. Investigate compound solubility in various vehicles and address potential in vivo administration issues proactively, saving significant time and resources.

Tip 3: Collaborate with formulation experts
Engage with formulation experts and collaborate closely with your R&D team. Their insights guide formulation decisions, ensuring chosen vehicles and excipients align with preclinical and clinical requirements, fostering a seamless transition from preclinical to clinical phases.

Ensuring Adequate Slide Preparation Can Mitigate Delays

Another prevalent challenge in in vivo work involves inadequate slide preparation, particularly when attempts are made to economize resources by not generating slides from all experimental groups or beyond the target tissue. This practice, while seemingly cost-effective, often leads to significant delays in data analysis and interpretation.

Tip 4: Adhere to comprehensive slide preparation for holistic insights
To mitigate delays associated with insufficient slide preparation, it is crucial to adopt a comprehensive approach. Generate slides not only from the target tissue but also from relevant control groups and non-target tissues. This ensures a holistic understanding of the compound’s effects and potential off-target impacts. While the initial cost may seem higher, the investment pays off in the form of accelerated data analysis and faster decision-making in later stages of the study.

Tip 5: Implement parallel processing and efficient workflows
To expedite slide preparation without compromising quality, consider implementing parallel processing and optimizing workflows. Utilize automation technologies where possible, streamline tissue processing steps and coordinate closely with pathology teams to ensure timely reads. Efficient collaboration between laboratory personnel involved in tissue fixation, embedding, sectioning and staining is crucial for maintaining a steady workflow, minimizing delays and obtaining comprehensive histopathological data.

Unanticipated Tissue Accumulation and Incomplete Excretion Can Present Unforeseen Challenges

A common challenge arises in IND studies when discrepancies between expected and observed radioactivity recovery occur during pharmacokinetic studies. This often indicates unexpected tissue accumulation, where the compound is not excreted as anticipated, potentially leading to altered pharmacokinetics and safety concerns.

Tip 6: Be proactive with metabolite identification
Conduct comprehensive metabolite identification studies early in the drug development process. By proactively characterizing metabolites formed during biotransformation, researchers can unveil potential pathways contributing to tissue accumulation.

Tip 7: Integrate radiolabeled studies
When encountering low recovery in non-radiolabeled PK screens, consider incorporating radiolabeled studies. This approach provides a more accurate assessment of the compound’s distribution, metabolism and excretion, offering insights into potential tissue sequestration.

Tip 8: Refine dosing strategies
Use metabolite identification data to refine dosing strategies. Adjusting the dosing regimen based on metabolite profiles can help mitigate the risk of tissue accumulation and enhance overall drug safety and efficacy.

Tip 9: Make informed decisions
The insights gained from metabolite identification testing empower informed decision-making. Understanding the compound’s metabolic fate aids in addressing issues related to unexpected tissue distribution, facilitating a smoother transition through IND-enabling work and subsequent stages of drug development.

Conclusion

In the dynamic realm of IND-enabling work, challenges encountered call for a proactive and strategic response. From careful formulation considerations to addressing slide preparation deficiencies to tackling unexpected tissue accumulation issues, each obstacle serves as a chance for refinement and improvement.

Formulating compounds with the end goal in mind is crucial, particularly when dealing with potential side-effects of excipients like DMSO. Choosing alternative excipients aligning with both animal and human safety considerations ensures a smoother transition into in vivo studies.

In slide preparation, a comprehensive mindset is key. Investing in thorough slide generation from diverse tissues, rather than solely focusing on the target, pays off through accelerated data analysis and more informed decision-making.

The unexpected issue of tissue accumulation during PK screens underscores the importance of metabolite identification testing. Proactively characterizing metabolites guides dosing strategy refinement, empowering informed decision-making throughout IND-enabling work and subsequent drug development stages.

In embracing these challenges, researchers can navigate IND-enabling work confidently, turning obstacles into opportunities for advancement toward the goal of developing safe and efficacious drugs.

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