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To identify chemotypes and lead compounds that have good pharmacokinetic and toxicological profiles, it has been recognized that studies that assess absorption, distribution, metabolism, and elimination (ADME) should be initiated as early as possible in the discovery process. Many ADME assays can be run in a high-throughput fashion, due principally to the widespread incorporation of liquid chromatography/mass spectrometry (LC-MS) and liquid chromatography/tandem mass spectrometry (LC-MS/MS). These techniques are preferred for in vitro ADME analyses due principally to enhanced sensitivity, selectivity, and ease of automation relative to traditional analytical methods.
Fig.1 By coordinating plating for ADME analyses at the same time as biological screening, ADME analyses are streamlined. (Kassel, 2004)
Common considerations for the ADME-related issues for therapeutic biologics include target-mediated clearance, FcRn recycling for Fc-containing proteins, immunogenicity, isoform heterogeneity, and metabolic stability, especially for relatively low molecular weight proteins.
Immunoassays, such as the Enzyme-linked immunosorbent assay (ELISA), are the most commonly used techniques for the quantification of proteins in serum due to their high sensitivity and specificity. Another technology particularly attractive for the bioanalysis of proteins is MS. The advantages of MS over ELISA include the improved selectivity between structurally similar peptides and proteins, reduced requirements for specific reagents, improved precision and accuracy, and a potentially higher throughput rate.
The labeling of therapeutic biologics is an invaluable technique that has been used extensively to analyze PK and metabolism, measure absolute tissue concentrations, and facilitate imaging studies. Today, the two main methods of radiolabeling proteins are halogenation and the complexation of metallic radioisotopes.
The value of in vitro ADME end-points has been well established. In many cases, the in vitro data are predictive of in vivo endpoints and can be used for internal decision-making. Even the FDA accepts the value of in vitro data and sometimes in vitro can be used to avoid having to perform certain clinical studies. In vitro ADME models have proven to be of great value in drug discovery and development. Data can be obtained that can potentially shed light on the fate of drugs in humans in a resource-sparing fashion. Frequently, these data are used by synthetic chemists in their quest to identify a compound with the desired human pharmacokinetic properties. The other advantage offered by central higher throughput in vitro ADME screening is that it provides a coherent set of data for building in silico ADME models. Reliable models are available and have been successfully integrated into drug discovery allowing synthetic chemists to incorporate ADME considerations prior to synthesis.
Fig.2 Schematic presentation of an ideal way to establish and utilise comprehensive profiling tools in drug discovery and development. (Wang, 2004)
ADME processes have been crucial in enhancing the possibility of the success of low molecular weight drugs, and it is expected that this will translate to novel biologics in the near future. The field of ADME of biologics is still rapidly expanding with new concepts and technologies. As these tools become more readily available in drug development settings, analyses that once were prohibitively complex and expensive will be used to help scientists develop better strategies aimed at optimizing the PK/ADME profiles of biologics.
Creative Biolabs is specializing in providing a comprehensive suite of pharmaceutical services. With our breadth of experience, vast access to scientific experts, and cutting-edge technology platform, we can provide you with a customizable solution that works to reduce your development timeline. We look forward to connecting with you and learning more about your specific needs, and how we can help.
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