Use PBPK Modeling To Design More Accurate Clinical Trials

By Life Science Connect Editorial Staff

The data available for trial design is produced during preclinical studies on cells and animals, which can leave much unknown in terms of how a drug will affect humans. These question marks include data on a drug’s oral absorption properties and insight into how the drug will be distributed within and eliminated from the body. To help prepare for any potential absorption risks during Phase 1 and 2 clinical trials, sponsors might consider leveraging physiologically based pharmacokinetic (PBPK) models to anticipate how drugs will behave in different physiological states.

Per the FDA, PBPK models “integrate drug substance and system physiology information into a mathematical modeling framework. Advancements in computation and medical science have fueled the increased use of PBPK models in drug development.”¹ PBPK models conduct simulations with physiology, patient populations, and drug properties to predict how a drug will interact with a specific biological state. Their usage is accepted and encouraged by the FDA to be leveraged as supplemental material for INDs, BLAs, and NDAs. By leveraging PBPK modeling to inform your trial protocol, you’ll gain better insight into potential absorption risks and obstacles that might pop up during in-human trials. As a result, you can strategize early and save time and money in the clinic.

Design A Modeling Strategy To Meet Your Needs

In clinical research, there is a decision problem that must be addressed via a clinical trial. Sponsors are considering how to safely deliver their drug to patients and reach the desired endpoints. Each clinical trial must have a clear objective behind it, and ideally, the objective will not overly complicate the protocol. By conducting PBPK research throughout your preclinical and early phase studies, you will be able to integrate all available modeling data into your trial to gain a better sense of the correct dosing and treatment regimen to take into Phase 3. Some of the common applications of PBPK modeling include applying knowledge from preclinical studies in animals to humans, assessing drug to drug interactions, making predictions for special populations including infants and children, and supplementing other advanced types of modeling.²

However, there is a philosophical element to modeling that might make it a challenge to implement. Though it is waning, there is still some skepticism associated with the value of PBPK findings since there may be a lack of knowledge associated with certain system elements, which could require presumptions or judgement calls.³ As the field grows, it is critical to continue to improve the evidence available to fortify PBPK models. To further aid this effort, the FDA has issued guidance on how to include PBPK study reports to bolster your filing, in which it recognizes the value of their usage: “Throughout a drug’s life cycle, PBPK model predictions can be used to support decisions on whether, when, and how to conduct certain clinical pharmacology studies, and to support dosing recommendations in product labeling.”⁴ In 2018, the FDA issued the Physiologically Based Pharmacokinetic Analyses — Format and Content report, which provides industry guidance for sponsors on how to format PBPK studies that they submit as part of their applications. If you are interested in leveraging PBPK models to supplement your studies, the FDA’s guidance is a useful tool for designing your strategy.

Secure Maximum Insight

Integrating all available information through modeling will enable understanding that is not otherwise possible or could be costly and taxing for patients in real-life studies. It will add more complexity to the study, but it is valuable complexity. Ultimately, the data gained via modeling could help produce a more effective and less burdensome trial experience for patients while saving time and resources for sponsors.

For more information about designing clinical trial protocols, watch the recent Clinical Leader Live event Trial Protocol Design Do’s and Don’ts.

References:

1. Center for Drug Evaluation and Research. (n.d.). Program of physiologically-based pharmacokinetic and pharmacodynamic modeling (PBPK program). U.S. Food and Drug Administration. https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/program-physiologically-based-pharmacokinetic-and-pharmacodynamic-modeling-pbpk-program
2. Kuepfer, L., Niederalt, C., Wendl, T., Schlender, J. F., Willmann, S., Lippert, J., Block, M., Eissing, T., & Teutonico, D. (2016). Applied Concepts in PBPK Modeling: How to Build a PBPK/PD Model. CPT: pharmacometrics & systems pharmacology, 5(10), 516–531. https://doi.org/10.1002/psp4.12134
3. Rowland, M., Lesko, L. J., & Rostami-Hodjegan, A. (2015). Physiologically Based Pharmacokinetics Is Impacting Drug Development and Regulatory Decision Making. CPT: pharmacometrics & systems pharmacology, 4(6), 313–315. https://doi.org/10.1002/psp4.52
4. Center for Drug Evaluation and Research. (2018, August). Physiologically based pharmacokinetic analyses — format and content. Food and Drug Administration. https://www.fda.gov/media/101469/download