ABSTRACT
This chapter discusses some basic principles of D–E–R characterization and describes how regulatory assessors may use this information to assess the suitability of dose for Phase III, inform the dosing strategy as stated in the Summary of Product Characteristics (SmPC). The analysis of D–E–R data and dose selection for confirmatory trials can be strengthened by longitudinal, model-based analysis. The model-based evaluation facilitates the assessment of cutoff glomerular filtration (GFR) values that require dose adjustment. Longitudinal exposure–response analyses can enable more efficient use of data than cross-sectional analyses. A cross-sectional analysis of dose or exposure versus response is usually performed by nonlinear regression and represents a straightforward way to assess the therapeutic window of a medicinal product. Cross-sectional analyses are sensitive to rate and severity of disease progression, which can impact apparent magnitude of drug effects. Guidelines on investigation of drug interactions emphasize that worst-case scenario with respect to magnitude of drug–drug interactions (DDI) effects should be evaluated.
