Adapting ADME and Pharmacokinetic Analysis to the Next Generation of Therapeutic Modalities

The development of multiple drug modalities over the past 20 years has dramatically expanded the therapeutic space for intervention in disease processes. Rather than being alternative therapeutic approaches, these modalities tend to be complimentary both in the scope of target space and the biological mechanisms harnessed for disease control. Realization of these therapeutic opportunities requires an understanding of the physiological, biochemical and biological barriers that control exposure to the drug target and resulting biological response. Consequently, successful application of ADME and PK/PD to characterization of novel therapeutics needs to consider the unique attributes conferred by the therapeutic modality and the desired and potential off-target biological responses. The discussion that follows provides examples of how barriers to exposure, and translation of exposure to efficacy can change across different modalities. Additionally, recommendations are made for ADME analysis in which biological barriers and mechanistic properties unique to specific modalities are used to focus ADME PK optimization and characterization. Preface: It is an honor to contribute to this issue of Journal of Pharmaceutical Science recognizing Per Artursson and his many accomplishments as a scientist and an educator. Meeting Per at a conference in 1989, I was impressed by his scientific agility, enthusiasm and breadth of knowledge. He showed a passion for science and courage to jump into unfamiliar scientific waters with research extending from microsphere formulations, the biology of drug absorption, cell biology of junctional complexes, delivery tools for gene therapy, and physicochemical analysis of structure transport relationships guiding intestinal absorption. Per has approached all these efforts with infectious enthusiasm, depth of knowledge, and a big smile. He shares his insights with students and colleagues leaving a path of wisdom to be followed. In recognition of Per’s adaptability and enthusiasm toward incorporating diverse strategies to address key challenges in the discovery and characterization of therapeutic molecules, I am happy to contribute this commentary on adapting ADME/PK characterization to address the novel challenges of emerging modalities.