title: Mathematical simulations for bioanalytical assay development: the (un-)necessity and (im-)possibility of free drug quantification.
abstract: For every drug development program it needs to be discussed whether discrimination between free and total drug concentrations is required to accurately describe its pharmacokinetic behavior. This perspective describes the application of mathematical simulation approaches to guide this initial decision based on available knowledge about target biology, binding kinetics and expected drug concentrations. We provide generic calculations that can be used to estimate the necessity of free drug quantification for different drug molecules. In addition, mathematical approaches are used to simulate various assay conditions in bioanalytical ligand-binding assays: it is demonstrated that due to the noncovalent interaction between the binding partners and typical assay-related interferences in the equilibrium, a correct quantification of the free drug concentration is highly challenging and requires careful design of different assay procedure steps.
authors.affiliation: Roche Diagnostics GmbH, pRED, Pharma Research & Early Development, Biologics Research, Department of Bioanalytics, Nonnenwald, 282377 Penzberg, Germany. roland.staack@roche.com
authors.forename: Roland F
authors.initials: RF
authors.lastname: Staack
authors.forename: Gregor
authors.initials: G
authors.lastname: Jordan
authors.forename: Julia
authors.initials: J
authors.lastname: Heinrich
mesh_terms: D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D001681:Biological Assay / Q000379:methods / Q000706:statistics & numerical data*; D001682:Biological Availability; D003198:Computer Simulation / Q000706:statistics & numerical data*; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D012107:Research Design
chemical_list: D000911:Antibodies, Monoclonal; D008024:Ligands