Prediction of active human dose: learnings from 20 years of Merck KGaA experience, illustrated by case studies

• Published in: Drug discovery today Vol. 25; no. 5; pp. 909 - 919
• Main Authors: Peters, Sheila Annie, Petersson, Carl, Blaukat, Andree, Halle, Joern-Peter, Dolgos, Hugues
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-05-2020
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2020.01.002

•A retrospective analysis of active human dose predictions for 15 drugs is reported.•Case studies illustrate the value of adhering to translational best practices.•Underestimation of active dose in 5 drugs is due to pharmacology rather than exposure.•Identified weaknesses are generic to the industry.•Predicted active dose range should reflect translational and exposure uncertainties.
High-quality dose predictions based on a good understanding of target engagement is one of the main translational goals in drug development. Here, we systematically evaluate active human dose predictions for 15 Merck KGaA/EMD Serono assets spanning several modalities and therapeutic areas. Using case studies, we illustrate the value of adhering to the translational best practices of having an exposure–response relationship in an appropriate animal model; having validated, translatable pharmacodynamic (PD) biomarkers measurable in Phase I populations in the right tissue; having a deeper understanding of biology; and capturing uncertainties in predictions. Given the gap in publications on the subject, we believe that the learnings from this unique diverse data set, which are generic to the industry, will trigger actions to improve future predictions.