Author: Erik Sjögren, Scientific Lead for PBPK and PBBM
Our physiologically based models may be used to navigate the complex interactions between drugs and physiology. To develop safe and effective therapies, we do need reliable maps of the territory our compounds will enter. However, when details of the maps are missing, difficult to read, or ambiguously explained, they are difficult to trust. The new ICH M15 guideline is a more than welcome addition; we finally have a common guidance on how to draw and communicate our maps.
Out of the currently available quantitative tools to guide us in drug development, Physiologically Based modeling, encompassing both PBPK and PBBM, makes the most explicit connection between anatomical structure, biological mechanisms, and drug disposition.
PB modeling treats the human body as a practical, interconnected system of blood flows, tissue volumes, and biological pathways. It allows us to mathematically describe the dynamics of an intervention, whether that is a solid dosage form dissolving in the gastrointestinal tract or a biologic modality being absorbed after a subcutaneous injection.
Our mathematical models are not the human body, but we may use them to navigate its physiological complexity.
The method has been around and evolved for decades, and over time it has been shown to be reliable in many areas of application. A dedicated PB modeler appreciates the logic of system possibilities and constraints as well as the plausibility of mechanistic interpretations.
However, dissecting these models to identify details and gain a true understanding of the structure and parameterization is not readily achieved. For other disciplines, the inner workings of a PB model may therefore look like an unnecessarily complex web of arbitrary assumptions and parameters, which leads to understandable skepticism. This hesitation has been compounded by a historic lack of transparency, and an unstructured way of reporting and describing both the models themselves and the modeling conduct.
The ability of PB modeling to simulate physiological reality offers immense practical value across drug development. For formulators, PBBM is a tool to optimize complex drug delivery. For clinical pharmacologists, PBPK provides a structured way to translate data across populations, safely accounting for biological diversity. To ensure that this methodology gains acknowledgment across scientific disciplines and is used to its full potential, we need to improve clarity. With the introduction of the new ICH M15 guideline this June, we now have harmonized expectations and a common language to do exactly that.
It is time that we in the PB community collectively commit to delivering high-quality and structured reporting. By making our work and approaches transparent and accessible, we can together support the collective trust and recognition of PB modeling.
Physiologically-based pharmacokinetics (PBPK) and physiologically-based biopharmaceutics modeling (PBBM) leverage accumulated knowledge to inform mechanistic analyses and achieve predictions beyond direct observations. These models integrate physiological and drug-specific parameters to optimize drug development, refine dosing strategies, and enhance risk assessment.
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