2.1.2. Assay Considerations
The use of free versus total PK assays to measure drug exposure and their impact on E-R relationships should be considered. It has been suggested that since free drug concentration is in excess from binding to targets and proteins it is unsuitable for E-R analyses.16 However, free drug concentration may also reflect active drug in the circulation that can bind to targets, and therefore be relevant in an E-R analysis. It is also thought that because monoclonal antibodies are dosed in excess of target ligands total concentration would approximate free concentrations, and selection of free versus total assay would not impact the E-R analysis.17 Developing bioanalytical assays to measure free concentrations for monoclonal antibodies also faces numerous technical challenges.17 As assays are studied and developed further potential impacts on E-R analyses should be evaluated.
E-R analyses for drugs with multiple analytes such as antibody-drug conjugates (ADCs) involve additional complexities. There is a limited understanding of whether exposure to the cytotoxic drug, monoclonal antibodies, ADC, or other intermediates provides the best correlation for E-R relationships.18, 19 The analyte driving response appears to vary across different ADCs, and this issue should be carefully considered in E-R analyses for ADCs.