ADME investigations of novel therapeutic modalities: challenges and opportunities 2025.

Introduction: Advancements in absorption, distribution, metabolism, and excretion (ADME) science and pharmacokinetics (PK) have reshaped the drug development landscape, markedly reducing clinical attrition due to unfavorable PK properties. As biotherapeutics become increasingly complex, dose optimization has emerged as a critical focus area to address remaining translation challenges, requiring comprehensive understanding and predictability of a drug candidate's PK and its relationships with pharmacodynamic (PD) effects.

Areas covered: Emerging biotherapeutic modalities such as antibody-drug conjugates (ADCs), blood-brain barrier-penetrating bispecific antibodies, adeno-associated virus (AAV) gene therapy, and oncolytic viruses (OVs) present unique challenges for ADME and PK investigations given their complex composition and the dynamic biological processes governing their disposition. This review explores the distinctive ADME characteristics of these four modalities, highlighting challenges they pose to traditional PK paradigms and innovative strategies being developed to enhance preclinical-to-clinical translation. Literature search for this review was performed via PubMed database search between 30 September 2025 and 6 February 2026.

Expert opinion: By integrating recent preclinical and clinical insights with advances in bioanalytical methods and mechanistic modeling, we present forward-looking perspectives on enabling more precise and effective dosing strategies for these complex modalities.