The rapid expansion of biomedical research over the past few decades has led to improved diagnostics, novel therapies, and a deeper understanding of the physiological mechanisms that drive drug development. As drug development progresses, researchers move beyond in vitro pharmacodynamics studies that focus on understanding cell behavior in isolated systems towards more accurate assessments of in vivo pharmacodynamics. In vivo pharmacodynamics studies consider how drug effects vary within various tissues and organs in a living organism over time. With this increased knowledge comes new challenges but also emerging trends for designing effective pharmacodynamic in vivo studies that could lead to breakthroughs in medical science! In this blog post, we will explore some of these recent developments in pharmacodynamics studies in animals and a case study for assessing pharmacodynamics with precision during preclinical studies.

At AniLocus, we provide clients with preclinical solutions designed to accomplish specific goals for their phase of drug development. With our clients, we establish the study goals, select the animal species, deisgn experiments, study schedules, and determine deliverables for each stage of the in vivo study. As a preclinical CRO, we assist Sponsors in advancing their drug development timeline by maximizing the study value. You need results yesterday, let’s get it done!

Finally, we’ll review strategies for setting up robust controls when approaching the interpretation of complex patient populations before closing in on a critical step that no biopharma or biotech professional should overlook, validating study parameters every step of the way! By covering these topics substantively, we hope to awaken ideas to facilitate better decision-making for future preclinical studies. So, let’s discuss in vivo pharmacodynamics!

What Is the Definition of Pharmacodynamics and Why Is Pharmacodynamics Important?

Pharmacodynamics refers to the study of how drugs interact with the body to produce their effects. It involves examining the mechanisms of drug action, including drug tolerance and interactions, to better understand how drugs work in the body. Pharmacodynamics is important because it helps healthcare professionals determine the appropriate dosage and regimen for a drug, as well as predict potential interactions with other medications. By understanding the pharmacodynamic properties of a drug, healthcare professionals can better tailor treatment plans to individual patients and achieve the best possible outcomes. Additionally, pharmacodynamics plays a critical role in drug development, helping researchers identify new drug targets and potential treatments for diseases.

How is In Vivo Pharmacodynamics Used in Drug Development?

In vivo pharmacodynamic studies are a crucial step in drug development, as they provide valuable information about how a potential therapeutic treatment interacts with a living system. These studies use animal models that are designed to simulate disease conditions found in humans. The goal of these studies is to gather data on how a drug interacts with a specific target in the body, such as a receptor or enzyme. By investigating the pharmacodynamics of a drug in vivo, researchers can make informed decisions about the efficacy and safety of a potential treatment for human use. In vivo animal studies used in translational models allow researchers to make predictions about how a drug will perform in human trials, which can ultimately lead to more efficient and effective drug development.

Benefits and Challenges of In Vivo Pharmacodynamics

In vivo pharmacodynamics plays a crucial role in the development of effective treatments for diseases. By studying how drugs interact with living systems, researchers can gain a better understanding of their efficacy and safety. However, there are challenges that come with studying in vivo pharmacodynamics, particularly when it comes to species differences and species-specific absorption and distribution. These factors can make it difficult to accurately extrapolate data from preclinical animal models to humans (Yadav et al., 2021). Despite these challenges, the benefits of in vivo pharmacodynamics cannot be ignored. It allows researchers to assess how drugs interact with complex biological systems, ultimately leading to more targeted and effective treatments for patients.

Methods for In Vivo Pharmacodynamics

A critical component of assessing a drug’s effectiveness is evaluating its pharmacodynamic properties in vivo. Various methods exist, including measuring biomarkers that are indicative of the drug’s biological activity within the body, histopathology methods that examine the tissue changes induced by dosing, and assays that quantitate drug exposure. These methods enable scientists to determine the bioactivity of a drug and establish its therapeutic range, allowing for optimized dosing and improved patient outcomes. By employing different pharmacodynamic techniques, researchers can gain a better understanding of a drug’s activity in vivo and pave the way for novel therapies.

Practical Applications of In Vivo Pharmacodynamics

In vivo Pharmacodynamics has wide practical applications that make it an essential aspect of drug discovery. A great example is for screening of drugs and biologics. It offers the ability to perform initial screening and preliminary assays which provides researchers with valuable information to assist in the selection of lead drug candidates. In vivo pharmacodynamics can also be used to determine appropriate dosing levels for efficacy. Simultaneously, the safety of the drug candidate can be assessed. Which is especially important for clinical trials. In summary, this technique enables scientists to evaluate the therapeutic potential of drugs in living organisms, ultimately leading to the development of safer and more effective therapeutics.

Case Study

The Use of In Vivo Pharmacodynamics in Development of a Combination Biologic to Treat Huntington’s Disease

The quest to find a cure for Huntington’s Disease (HD) has motivated scientists to explore various avenues of treatment. HD is a genetic neurodegenerative disorder that causes neuronal death in the striatum. The striatum is a region of the brain involved in movement, mood, and cognition. When these neurons die, patients develop uncontrolled body movements, memory loss, and severe mood swings. The disorder is progressive, and patients may develop difficulty chewing and swallowing, speaking, and become prone to stumbling or falling. Therapy for HD treats the symptoms but there is no cure for the disease. Within the last two decades, researchers have identified unique approaches for the use of human-derived embryonic stem cells (hESC) coupled with adeno-associated virus (AAV) viral therapy targeting the mutant huntingtin protein  (Niclis J et al, 2009; So K et al, 2020; Islam J et al, 2021).

At Anilocus, we can assist in your product development by providing rodent models of Huntington’s Disease previously characterized that demonstrate the disease’s pathogenesis and potential pharmacological interventions. As a standard, we utilize well-documented transgenic and conditional animal models of disease to determine dosing, safety, and efficacy of your drug product. Not all diseases have well established animal models. Rare diseases are complex, and many models have yet to be established. That’s not a problem for Team Anilocus. We will create and validate animal models that are translational and applicable to your therapeutic.

By utilizing the Anilocus expertise, you can better understand how drugs interact with living systems and infer their efficacy in ameliorating symptoms. Together, we learn how your novel techniques and our high-standard approaches make a significant contribution to drug development in treating complex diseases.

Conclusions for In Vivo Pharmacodynamics Studies

In conclusion, the combination of pharmacodynamics and drug development inspires effective new treatments for unmet medical needs. It is essential to understand the dose-response relationship of a drug before it can be developed. In vivo pharmacodynamics is integral in elucidating this relationship and providing quantitative, translational data on clinical parameters. Despite the advantages of in vivo techniques, there are challenges associated with the disease complexity, species-specific differences, and predictive responses. Fortunately, in recent years, methods have improved in vivo pharmacodynamic studies enabling them to become more translational.

The advancements provide investigators with opportunities to test different drug products at once, thus optimizing the drug discovery process and saving time when researching potential drugs. As demonstrated through the example of a combination cell-gene therapeutic for Huntington’s Disease presented here, understanding how specific drugs function in animal disease models and differ from the isolated cell systems is crucial to the AAV (gene) and cell line screening and production process. These steps are essential in designing preclinical models that predict human response outcomes for efficacy evaluation and safety assessment. Ultimately, such elements enable researchers to identify clinically relevant biochemical pathways or targets that lead to successful pharmaceutical production of therapeutics.

At Anilocus, we are excited to work with you in the preclinical phase of drug development. Let’s discuss preclinical solutions for your upcoming in vivo pharmacodynamics study – contact us today to get started!

References

  1. Cui, C. S., Kumar, V., Gorman, D. M., Clark, R. J., Lee, J. D., & Woodruff, T. M. (2021). In Vivo Pharmacodynamic Method to Assess Complement C5a Receptor Antagonist Efficacy. ACS pharmacology & translational science, 5(1), 41–51. https://doi.org/10.1021/acsptsci.1c00227.
  2. Islam, J., So, K. H., Kc, E., Moon, H. C., Kim, A., Hyun, S. H., Kim, S., & Park, Y. S. (2021). Transplantation of human embryonic stem cells alleviates motor dysfunction in AAV2-Htt171-82Q transfected rat model of Huntington’s disease. Stem cell research & therapy, 12(1), 585. https://doi.org/10.1186/s13287-021-02653-7.
  3. Niclis, J., Trounson, A. O., Dottori, M., Ellisdon, A., Bottomley, S. P., Verlinsky, Y., & Cram, D. (2009). Human embryonic stem cell models of Huntington disease. Reproductive biomedicine online, 19(1), 106–113. https://doi.org/10.1016/s1472-6483(10)60053-3.
  4. So, K. H., Choi, J. H., Islam, J., Kc, E., Moon, H. C., Won, S. Y., Kim, H. K., Kim, S., Hyun, S. H., & Park, Y. S. (2020). An Optimization of AAV-82Q-Delivered Rat Model of Huntington’s Disease. Journal of Korean Neurosurgical Society, 63(5), 579–589. https://doi.org/10.3340/jkns.2019.0182.
  5. Yadav, J., El Hassani, M., Sodhi, J., Lauschke, V. M., Hartman, J. H., & Russell, L. E. (2021). Recent developments in in vitro and in vivo models for improved translation of preclinical pharmacokinetics and pharmacodynamics data. Drug metabolism reviews, 53(2), 207–233. https://doi.org/10.1080/03602532.2021.1922435.