Translational Modeling Strategies for Orally Administered Drug Products: Academic, Industrial and Regulatory Perspectives.

During non-clinical and clinical development of a new molecular entity (NME), modeling and simulation (M&S) are routinely used to predict the exposure and pharmacokinetics (PK) of the drug compound in humans. The basic methodology and output are generally understood across all functional disciplines. However, this understanding is mostly restricted to traditional methods such as those in simplified kinetic models and void of adequate mechanistic foundation to address questions beyond the observed clinical data. In the past two decades, alternative and more mechanistic methods, particularly for describing absorption, distribution, excretion and metabolism (ADME) of drugs have been developed and applied under the general umbrella of physiologically-based pharmacokinetic (PBPK) methods. Their mechanistic nature gives the ability to ask many other questions which were not traditionally asked and provide some logically and evidenced-based potential answers. Whilst traditional PK methods are mainstream and understood by most scientists, mechanistic absorption models alongside other PBPK approaches are still deemed eclectic, despite making significant strides in the fundamental science as well as regulatory acceptance. On November 3rd, a short course was held at the annual American Association of Pharmaceutical Scientists (AAPS) meeting in San Antonio, Texas. The different talks were tailored to provide a basis or rationale for the subject, introduction to fundamental principles with historical perspective, a critique of the state-of-the-art, examples of successful application of the methods across different phases of the drug development process and the specific standards these mechanistic models should meet to be fully reliable from a regulatory perspective.