ADME of therapeutic proteins
Review of critical factors, analytical methods and experimental approaches
Therapeutic proteins have revolutionized the treatment of many diseases and have a promising future with more than forty monoclonal antibodies and Fc-fusion therapeutics already on the US market and over 400 more in clinical development stages. Therapeutic proteins are, however, hit hard by a high attrition rate, mainly to poor efficacy, which results in only one in ten making it to market. Increasing the success rate relies on many factors, including the study of absorption, distribution, metabolism and excretion (ADME), as Jay Tibbitts at UCB Celltech, UK, and his coauthors point out in their extensive review on the subject.
While development of therapeutic proteins routinely includes in vivo pharmacokinetics, pharmacodynamics and efficacy studies, ADME studies are also critical in the discovery and development of biologics and need more study. This review covers factors affecting ADME, such as size and charge, modifications and target binding, technologies and methods for analysis, and experimental approaches (see Reference).
The nature of biologics puts special demands on analytical techniques. Most therapeutic biologics have limited distribution in tissues, which means that ADME studies are primarily in vivo. ELISA is the most common method for measurement in serum due to its high sensitivity and specificity, but, as the authors indicate, the method is too labor intensive and expensive for large-scale studies. This has prompted the development of platforms such as Gyrolab system, and mass spectrometry (MS) and liquid-chromatography-mass spectrometry (LC/MS). Assay sensitivity and specificity are critical factors in designing ADME studies, with the need to accurately and precisely measure analytes at pharmacologically relevant levels and in matrices that are often challenging.
The authors conclude by stating that ADME processes have been crucial in the success of low molecular weight drugs and can be expected to be critical for biologics in the future. This will require supporting internal decision-making and regulatory acceptance with high quality data generated by new analytical methods to help optimize the PK/ADME profiles of next-generation biologics.
Find out more about how Gyrolab systems support the development of biotherapeutics:
Jay Tibbitts, David Canter, Ryan Graff, Alison Smith & Leslie A. Khawli (2015): Key factors influencing ADME properties of therapeutic proteins: A need for ADME characterization in drug discovery and development, mAbs, DOI: 10.1080/19420862.2015.1115937