Direct bioanalysis or indirect calculation of target engagement and free drug exposure: do we apply double standards?

Bioanalysis

Roche Pharma Research & Early Development (pRED), Pharmaceutical Sciences, Bioanalysis & Biomarkers, Roche Innovation Center Munich, Roche Diagnostics GmbH, Nonnenwald 2, Penzberg, 82377, Germany.

Published: January 2023

Analysis of "free" drug/target concentrations is important to set up appropriate pharmacokinetic-pharmacodynamic models, to evaluate active-drug exposure and target engagement. Such "free-analyte" determination could be done by direct bioanalysis using an appropriate "free-analyte" assay. Development of "free" assays is often considered challenging from a technological and regulatory perspective. The application of a "total-total" approach, where the "free-analyte" concentration is determined mathematically, is considered a more convenient option. In this perspective, we examine and discuss the challenges of this "total-total" approach, from the affinity data, the importance of applying an appropriate "total" assay, the impact of additional binding partners and the variability of the total drug/target assays and their impact on the quality and variability of the final "free-analyte" dataset.

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http://dx.doi.org/10.4155/bio-2022-0246DOI Listing

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