Strategy for streamlining antibody–drug conjugate pharmacokinetic assays

Antibody-drug conjugates (ADCs) have reemerged as a transformative therapeutic modality, with over a dozen approvals and hundreds of candidates in clinical development. Historically, ADC pharmacokinetic (PK) evaluation required measuring all constituent components - total antibody (TAb), conjugated antibody (ADC), or conjugated payload, free payload, and major metabolites. This comprehensive approach led to a significantly higher bioanalytical (BA) investment, increased patient blood volume requirements, and far more resources than those needed for monoclonal antibody (mAb) therapeutics or small molecule drugs. In 2024, the US Food and Drug Administration (FDA) issued guidance encouraging a more streamlined, data-driven approach to ADC PK assessment in clinical development, including the potential to omit certain analytes when scientifically justified. While this guidance represents a pivotal shift, adoption across the industry has been slow, and few examples of successful assay reduction have been publicly shared. In this perspective, we examine the scientific and regulatory rationale for simplifying ADC PK strategies. We also propose a pragmatic framework for reducing assays - grounded in clinical relevance, early-phase data, and platform knowledge - that seeks to reduce complexity without compromising patient safety or data integrity.