Strategies to address drug interaction potential for antibody-drug conjugates in clinical development

Antibody–drug conjugates (ADCs) are a unique class of therapeutic proteins with both small and large molecular components. In vivo, ADCs are processed to multiple clinically relevant analytes, each with distinct PK properties. This increases the complexity for ADC drug interaction (DI) assessment. Furthermore, given the usually narrow therapeutic range for ADCs, a thorough risk assessment is essential to establish benefit/risk for patients. Therefore, an early understanding of the ADC catabolism and elimination pathways and cytochrome P450 reaction phenotyping, cytochrome P450 inhibition and induction potential, transporter interaction and inhibition potential for the cytotoxic drug catabolites assessed by in vitro and preclinical studies is essential. This information would be integrated with the clinical PK and PD properties of the ADC-related analytes for a theoretical risk assessment of ADC DI in combination therapy. ADC DI assessment in clinical studies will further support the theoretical risk assessment and the conclusions for the labeling statement.

Presently, there is no comprehensive review to assist in determining the best risk assessment strategy to evaluate the antibody–drug conjugate (ADC)-drug interaction (DI) potential when an ADC is given in combination with other drugs. We therefore summarized an ADC DI risk assessment strategy based on the current knowledge in this field to help provide guidance in this area.

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