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.